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Abstract:

Disclosed herein are new salts and polymorphs of desazadesferrithiocin
polyether (DADFT-PE) analogues, as well as pharmaceutical compositions
comprising them and their application as metal chelation agents for the
treatment of disease. Methods of chelation of iron and other metals in a
human or animal subject are also provided for the treatment of metal
overload and toxicity.

Claims:

1. A solid salt of Formula II: ##STR00028## wherein: m is an integer
from 0 to 8; n is an integer from 0 to 8; and X is a counterion chosen
from calcium hydroxide, magnesium hydroxide, potassium, sodium, zinc, and
piperazine; or a polymorph thereof.

60. The salt or polymorph thereof as recited in claim 1, wherein m is 2
and n is 3.

61. The salt or polymorph thereof as recited in claim 1, wherein m is 2
and n is 2.

62. A polymorph of the salt as recited in claim 1, wherein the polymorph
is a stoichiometric hydrate of the zinc salt.

63. The polymorph as recited in claim 62, wherein said polymorph is the
monohydrate.

64. A pharmaceutical composition comprising the salt or polymorph thereof
as recited in claim 1, together with at least one pharmaceutically
acceptable excipient.

65. The pharmaceutical composition as recited in claim 64, wherein the
salt or polymorph thereof has structural formula II ##STR00029##
wherein m is 2 and n is 3; and the counterion X is chosen from calcium
hydroxide, magnesium hydroxide, potassium, sodium, zinc, and piperazine.

66. The pharmaceutical composition as recited in claim 64, wherein the
salt is magnesium
(S)-2-(2-hydroxy-3-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)-4-methyl--
4,5-dihydrothiazole-4-carboxylate hydroxide, or a polymorph thereof.

67. A pharmaceutical composition comprising magnesium
(S)-2-(2-hydroxy-3-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)-4-methyl--
4,5-dihydrothiazole-4-carboxylate hydroxide, or a polymorph thereof,
together with at least one pharmaceutically acceptable excipient.

Description:

[0001] This application claims the benefit of priority of U.S. provisional
applications No. 61/080,572, filed Jul. 14, 2008, and No. 61/152,572,
filed Feb. 13, 2009, the disclosures of which are hereby incorporated by
reference as if written herein in their entirety.

[0002] Disclosed herein are new salts and polymorphs of
desazadesferrithiocin polyether (DADFT-PE) analogues, as well as
pharmaceutical compositions comprising them and their application as
metal chelation agents for the treatment of disease. Methods of chelation
of iron and other metals in a human or animal subject are also provided
for the treatment of metal overload and toxicity.

[0003] Metal ions are critical to the proper functioning of living
systems. Ions such as Fe3+, Zn2+, Cu2+, Ca2+, and
Co3+, to name but a few, can be found in the active sites of over a
third of known enzymes and other functional proteins such as RNA
polymerase, DNA transcription factors, cytochromes P450s, hemoglobin,
myoglobin, and coenzymes such as vitamin B12. There, these metals
serve to facilitate oxidation and reduction reactions, stabilize or
shield charge distributions, and orient substrates for reactions.

[0004] However, the body has a limited ability to absorb and excrete
metals, and an excess can lead to toxicity. As one example, an excess of
iron, whether derived from red blood cells chronically transfused,
necessary in such conditions such as beta thalassemia major, or from
increased absorption of dietary iron such as hereditary hemochromatosis
can be toxic through the generation by iron of reactive oxygen species
such as H2O2. In the presence of Fe2+, H2O2 is
reduced to the hydroxyl radical (HO), a very reactive species, a process
known as the Fenton reaction. The hydroxyl radical reacts very quickly
with a variety of cellular constituents and can initiate free radicals
and radical-mediated chain processes that damage DNA and membranes, as
well as produce carcinogens. The clinical result is that without
effective treatment, body iron progressively increases with deposition in
the liver, heart, pancreas, and elsewhere. Iron accumulation may also
produce (i) liver disease that may progress to cirrhosis, (ii) diabetes
related both to iron-induced decreases in pancreatic β-cell
secretion and increases in hepatic insulin resistance and (iii) heart
disease, still the leading cause of death in beta thalassemia major and
other anemias associated with transfusional iron overload.

[0005] As another example, ions with little or no endogenous function may
find their way into the body and effect damage. Heavy metal ions such as
Hg2+ can replace ions such as Zn2+ in metalloproteins and
render them inactive, resulting in serious acute or chronic toxicity that
can end in a patient's death or in birth defects in that patient's
children. Even more significantly, radioactive isotopes of the lanthanide
and actinide series can visit grave illness on an individual exposed to
them by mouth, air, or skin contact. Such exposure could result not only
from the detonation of a nuclear bomb or a "dirty bomb" composed of
nuclear waste, but also from the destruction of a nuclear power facility.

[0006] Agents for the chelation and decorporation of metal ions in living
organisms have been previously disclosed and are in clinical use. A
variety of ligands have been shown to bind Fe3+, Pu4+,
Th4+, Am4+, Eu3+ and U4+, for example. Traditional
standard therapies include the use of agents such as deferoxamine (DFO,
N'-[5-(acetyl-hydroxy-amino)pentyl]-N-[5-[3-(5-aminopentyl-hydroxy-carbam-
oyl)propanoylamino]pentyl]-N-hydroxy-butane diamide), a very effective
metal chelator. DFO is, unfortunately, not orally bioavailable and must
therefore be parenterally dosed IV, IP, or SC, and once in the
bloodstream has a very short half life. Diethylene triamine pentaacetic
acid (DTPA) is approved for use in the treatment of lanthanide and
actinide poisoning, but also cannot be dosed orally, ideally should be
given very quickly following contamination, and presents with a number of
side effects. For these reasons, continuous infusion of these agents is
often required, and particularly in the case of chronic disorders,
patient compliance can be a problem. A thorough review of publicly
available art will show that although effective chelation agents have
been available for decades, oral bioavailability has historically been a
desirable trait in successive next-generation agents.

[0007] More recently, orally active agents have become available for use
in the treatment of metal overload. Deferiprone
(3-hydroxy-1,2-dimethylpyridin-4(1H)-one) has been used in Europe and
some other countries as an oral agent for the treatment of transfusional
iron overload in the setting of beta thalassemia and other disorders, but
the drug is not approved for use in the United States and Canada, and
reported side effects including agranulocytosis have in many cases
relegated it to second-line therapy. Deferasirox (Exjade,
[4-[(3Z,5E)-3,5-bis(6-oxo-1-cyclohexa-2,4-dienylidene)-1,2,4-triazolidin--
1-yl]benzoic acid, Novartis) is currently the only oral agent approved in
the United States for chelation therapy. Even still, nephrotoxicity
leading to renal failure and cytopenia have been reported by the Food and
Drug Administration as side effects to Deferasirox oral suspension
tablets. Moreover, neither of these agents is as efficacious a chelator
as DFO. Clearly, a need still exists in the art for long-lasting, orally
active metal chelators with reduced toxicity for the treatment of iron
overload secondary to transfusion or excessive intestinal absorption and
other metal overload disorders.

[0008] Analogues of desferrithiocin, or
[(S)-4,5-dihydro-2-(3-hydroxy-2-pyridinyl)4methyl-4thiazo]carboxylic acid
(DFT) have been shown to form 2:1 hexacoordinate complexes with Fe3+
and Th4+. These ligands, when administered either subcutaneously
(SC) or orally (PO) to rodents, dogs, and primates, have been shown to
clear iron very efficiently, and to decorporate uranium from rodents when
given SC, PO, or intraperitoneally, with particularly profound effects in
the kidney. Although development of DFT itself had been discontinued due
to nephrotoxicity, one of these ligands
(S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic
acid, or (S)-4'-(HO)-DADFT, has proven to be an effective chelation agent
with the additional benefit of being orally available, and as of the
present is believed to be in clinical trials. A very recent paper
discloses the design and testing of DADFT analogues substituted by a
polyether group at the 3', 4', and 5' positions (Bergeron R J et al., J
Med. Chem. 2007 Jul. 12; 50(14):3302-13). Polyether analogues had
uniformly higher iron-clearing efficiencies (ICEs) than their
corresponding parent ligands in rodents and in serum albumin binding
studies, with the 3'-DADFT-PE analogue
(5)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-t-
hiazolecarboxylic acid showing the most promising ICE in rodents and
non-human primates.

[0009] Though DADFT polyethers as a class of compounds appear promising in
the search for improved metal chelation agents, much work remains to be
done in the characterization, development, and selection of a compound
suitable for use in humans. Room for improvement is still apparent in the
design of analogues and salt forms thereof which have the optimal balance
of ICE, bioavailability, favorable toxicology, and other attributes for
the purpose of providing safe and effective compounds which will be easy
to use by patients and clinicians alike. Additionally, many factors still
influence the suitability of a compound as a pharmaceutical agent in
general. To be suitable for manufacture and distribution, a compound
should be capable of being produced in yield and purity, or should be
capable of being purified from co-products. Such a compound should also
be stable, i.e., should not degrade over time into potentially inactive
or toxic compounds, or even transform into alternate crystalline forms
having different and potentially quite relevant dissolution, absorption,
and other properties.

[0010] Disclosed herein are novel salts and polymorphs of these polyether
analogues and derivatives thereof. Pharmaceutical formulations comprising
the salts and polymorphs are also disclosed, as well as methods for the
treatment of diseases and conditions related to toxicity which is a
result of an acute or chronic excess of metal in a human or animal body.
Certain salts disclosed herein are stable, pure, and soluble, indicating
likely bioavailability.

[0018] Certain compounds, salts, and polymorphs disclosed herein may
possess useful metal chelating activity, and may be used in the treatment
or prophylaxis of a disease or condition in which metal overload or
toxicity plays an active role. Thus, in broad aspect, certain embodiments
also provide pharmaceutical compositions comprising one or more
compounds, salts, or polymorphs disclosed herein together with a
pharmaceutically acceptable carrier, as well as methods of making and
using the compounds, salts, and polymorphs and their compositions.
Certain embodiments provide methods for chelating metals in living
systems. Other embodiments provide methods for treating disorders and
symptoms relating to metal toxicity in a patient in need of such
treatment, comprising administering to said patient a therapeutically
effective amount of a compound or composition as disclosed herein, or a
salt or polymorph thereof. Also provided is the use of certain compounds,
salts, and polymorphs disclosed herein for use in the manufacture of a
medicament for the treatment of a disease or condition ameliorated by the
chelation or decorporation of metals.

BRIEF DESCRIPTION OF THE DRAWINGS

[0019] FIG. 1. XRPD Patterns of Salts of (S)-3'-(OH)-DADFT-PE: the zinc,
potassium, piperazine, magnesium, sodium, and calcium salts (from top to
bottom). Degrees θ-2θ on the abscissa are plotted against an
arbitrary Y value on the ordinate.

[0020] FIG. 2. Physical stability study of (S)-3'-(OH)-DADFT-PE potassium
salt, isolated as the Form A polymorph (top spectrum), the Form B (middle
spectrum) and the Form C (bottom spectra) salts. Degrees θ-2θ
on the abscissa are plotted against an arbitrary Y value on the ordinate.

[0025] FIG. 7. XRPD Patterns of (S)-3'-(OH)-DADFT-PE magnesium salt: the
amorphous form and form A (from top to bottom). Degrees θ-2θ
on the abscissa are plotted against an arbitrary Y value on the ordinate.

[0026] FIG. 8. XRPD Pattern of (S)-3'-(OH)-DADFT-PE magnesium salt form B.
Degrees θ-2θ on the abscissa are plotted against an arbitrary
Y value on the ordinate.

[0027] FIG. 9. XRPD Pattern of (S)-3'-(OH)-DADFT-PE magnesium salt form C.
Degrees θ-2θ on the abscissa are plotted against an arbitrary
Y value on the ordinate

[0030] FIG. 12. XRPD Patterns of Salts of (S)-4'-(OH)-DADFT-PE: the
arginine A, calcium A, calcium B, magnesium A, sodium A, and HCl salts
(from top to bottom). Degrees θ-2θ on the abscissa are
plotted against an arbitrary Y value on the ordinate.

[0031] FIG. 13. XRPD Patterns of Salts of (S)-4'-(OH)-DADFT-PE: the lysine
A, piperazine A, NMG A, and tromethamine A salts (from top to bottom).
Degrees 0-20 on the abscissa are plotted against an arbitrary Y value on
the ordinate.

[0032] FIG. 14. XRPD Patterns of Salts of (S)-4'-(OH)-DADFT-PE: the
calcium A, magnesium A, lysine A, NMG A, and tromethamine A salts (from
top to bottom). Degrees θ-2θ on the abscissa are plotted
against an arbitrary Y value on the ordinate.

[0051] In further embodiments, R6 and R7 are independently
chosen from hydrogen and methoxy.

[0052] In further embodiments, R1 is hydroxy.

[0053] In further embodiments, R2, R3, R4, and R5 are
independently chosen from hydrogen and
CH3O((CH2)n--O)m--.

[0054] In further embodiments, salts and polymorphs thereof have
structural formula II:

##STR00003##

[0055] In further embodiments, salts and polymorphs thereof have
structural formula IIa:

##STR00004##

[0056] In further embodiments, the counterion X is chosen from calcium,
magnesium, potassium, sodium, zinc, and piperazine.

[0057] In further embodiments, m is 2 and n is 3.

[0058] In further embodiments, the salt is the magnesium salt, or a
polymorph thereof.

[0059] In further embodiments, the salt is magnesium
3'-desazadesferrithiocin polyether hydroxide or a polymorph thereof.

[0060] In further embodiments, said polymorph of magnesium
3'-desazadesferrithiocin polyether hydroxide is Form A.

[0061] In further embodiments, said Form A has an X-ray powder diffraction
pattern which is at least 70%, at least 80%, at least 90%, or at least
95% identical to that shown in FIG. 7.

[0062] In other embodiments, said polymorph of magnesium
3'-desazadesferrithiocin polyether hydroxide is Form B.

[0063] In further embodiments, said Form B has an X-ray powder diffraction
pattern which is at least 70%, at least 80%, at least 90%, or at least
95% identical to that shown in FIG. 8.

[0064] In further embodiments, said Form B has a differential scanning
calorimetry (DSC) thermogram which is at least 70%, at least 80%, at
least 90%, or at least 95% identical to that shown in FIG. 10.

[0065] In further embodiments, said Form B has a dynamic vapor
sorption/desorption (DVS) spectrum which is at least 70%, at least 80%,
at least 90%, or at least 95% identical to that shown in FIG. 11.

[0066] In other embodiments, said polymorph of magnesium
3'-desazadesferrithiocin polyether hydroxide is Form C.

[0067] In further embodiments, said Form C has an X-ray powder diffraction
pattern which is at least 70%, at least 80%, at least 90%, or at least
95% identical to that shown in FIG. 9.

[0068] In other embodiments is provided an amorphous form of magnesium
3'-desazadesferrithiocin polyether hydroxide.

[0069] In further embodiments, said amorphous form has an X-ray powder
diffraction pattern which is at least 70%, at least 80%, at least 90%, or
at least 95% identical to that shown in FIG. 7.

[0070] In further embodiments, the salt or polymorph thereof has an
aqueous solubility at near-physiologic pH of between 0.3 mg/ml and 70
mg/ml.

[0071] In further embodiments, the salt or polymorph thereof has an
aqueous solubility at near-physiologic pH of ≧40 mg/ml.

[0072] In further embodiments, the salt or polymorph thereof has an
aqueous solubility at near-physiologic pH of ≧50 mg/ml.

[0073] In further embodiments, the salt or polymorph thereof has an
aqueous solubility at simulated gastric pH of 0.05 mg/ml-250 mg/ml.

[0074] In further embodiments, the salt or polymorph thereof has an
aqueous solubility at near-physiologic pH of between 0.3 mg/ml and 70
mg/ml and having an aqueous solubility at simulated gastric pH of 0.05
mg/ml-250 mg/ml.

[0075] In further embodiments, the salt is the potassium salt or a
polymorph thereof.

[0076] In further embodiments are provided the Form A polymorph of the
potassium (S)-3'-DADFT-PE salt, having an XRPD pattern substantially
similar to that shown in the upper curve of FIG. 2.

[0077] In further embodiments, the salt is the potassium salt, or a
polymorph thereof.

[0085] In further embodiments, salts and polymorphs thereof have
structural formula IIIa:

##STR00006##

[0086] In further embodiments, X is chosen from lysine, NMG, tromethamine,
calcium, and magnesium.

[0087] In further embodiments is provided a polymorph of a salt of Formula
III, wherein the polymorph is a stoichiometric hydrate of the sodium
salt.

[0088] In further embodiments, said polymorph is the monohydrate.

[0089] In further embodiments, said polymorph is the dihydrate.

[0090] In further embodiments is provided tromethamine
4'-desazadesferrithiocin polyether hydroxide, or a polymorph thereof.

[0091] In further embodiments, the salt of Formula III has a X-ray powder
diffraction pattern which is at least 70%, at least 80%, at least 90%, or
at least 95% identical to that shown in FIG. 13.

[0092] In further embodiments, the salt of Formula III has a differential
scanning calorimetry thermogram which is at least 70%, at least 80%, at
least 90%, or at least 95% identical to that shown in FIG. 19.

[0093] In further embodiments, the salt of Formula III has a dynamic vapor
sorption/desorption (DVS) spectrum which is at least 70%, at least 80%,
at least 90%, or at least 95% identical to that shown in FIG. 20.

[0094] In further embodiments, the salt of Formula III has an aqueous
solubility at near-physiologic pH of between 0.3 mg/ml and 150 mg/ml.

[0100] The compound of formula VI may exist in three substantially
crystalline polymorphic forms referred to hereafter as Forms A-C, as well
as an amorphous form, which differ from each other in their stability,
physicochemical properties, and spectral characteristics.

[0113] In certain embodiments, characterizing data for a compound of
formula VII as obtained by X-ray powder diffraction (XRPD) is shown in
FIG. 13.

[0114] In certain embodiments, characterizing data for a compound of
formula VII as obtained by differential scanning calorimetry (DSC) is
shown in FIG. 19.

[0115] In certain embodiments, characterizing data for a compound of
formula VII as obtained by vapor sorption/desorption (DVS) is shown in
FIG. 20.

[0116] In certain embodiments are provided salts of structural formula II
and polymorphs thereof having an aqueous solubility at near-physiologic
pH of between 0.3 mg/ml and 70 mg/ml.

[0117] In certain embodiments are provided salts of structural formula II
and polymorphs thereof having an aqueous solubility at near-physiologic
pH of >40 mg/ml.

[0118] In certain embodiments are provided salts of structural formula II
and polymorphs thereof having an aqueous solubility at near-physiologic
pH of >50 mg/ml.

[0119] In certain embodiments are provided salts of structural formula II
and polymorphs thereof having an aqueous solubility at simulated gastric
pH of 0.05 mg/ml-250 mg/ml.

[0120] In certain embodiments are provided salts of structural formula II
and polymorphs thereof having an aqueous solubility at near-physiologic
pH of between 0.3 mg/ml and 70 mg/ml and having an aqueous solubility at
simulated gastric pH of 0.05 mg/ml-250 mg/ml.

[0121] In certain embodiments are provided salts of structural formula II
and polymorphs thereof having an aqueous solubility at near-physiologic
pH (˜7.4) of between 0.3 mg/ml and 70 mg/ml and having an aqueous
solubility at simulated gastric pH (˜pH 1) of 0.05 mg/ml-250 mg/ml.

[0122] In certain embodiments are provided salts of structural formula III
and polymorphs thereof having an aqueous solubility at near-physiologic
pH (˜7.4) of between 0.3 mg/ml and 150 mg/ml.

[0123] Also provided are pharmaceutical compositions comprising the salt
or polymorph thereof as disclosed herein together with at least one
pharmaceutically acceptable excipient.

[0125] wherein [0126] m is 2 and n is 3; and [0127] wherein the
counterion X is chosen from calcium, magnesium, potassium, sodium, zinc,
and piperazine.

[0128] In further embodiments is provided a pharmaceutical composition
comprising magnesium 3'-desazadesferrithiocin polyether hydroxide
(Mg(OH).3'-DADFT-PE), or a polymorph thereof, together with at least one
pharmaceutically acceptable excipient.

[0130] wherein [0131] m is 2 and n is 3; and [0132] the counterion X is
chosen from lysine, NMG, tromethamine, calcium, magnesium.

[0133] In further embodiments is provided a pharmaceutical composition
comprising tromethamine 4'-desazadesferrithiocin polyether hydroxide
(tromethamine.4'-DADFT-PE) or a polymorph thereof, together with at least
one pharmaceutically acceptable excipient.

[0134] In certain embodiments, the pharmaceutical composition comprises
magnesium 3'-desazadesferrithiocin polyether hydroxide
(Mg(OH).3'-DADFT-PE), or a polymorph thereof, together with at least one
pharmaceutically acceptable excipient.

[0135] In certain embodiments, the pharmaceutical composition comprises
tromethamine 4'-desazadesferrithiocin polyether hydroxide
(tromethamine.4'-DADFT-PE) or a polymorph thereof, together with at least
one pharmaceutically acceptable excipient.

[0136] In certain embodiments are provided a method of treating a
pathological condition responsive to chelation, sequestration, or
elimination of a trivalent metal in a subject comprising administering to
the subject a therapeutically effective amount of a salt or polymorph
thereof as disclosed herein 1.

[0137] In further embodiments, said trivalent metal is iron.

[0138] In further embodiments, said pathological condition is iron
overload.

[0139] In further embodiments, said pathological condition is the result
of mal-distribution or redistribution of iron in the body.

[0140] In further embodiments, said pathological condition is chosen from
atransferrinemia, aceruloplasminemia, and Fredreich's ataxia.

[0141] In further embodiments, said pathological condition is the result
of transfusional iron overload.

[0143] In further embodiments, said pathological condition is a hereditary
condition resulting in the excess absorption of dietary iron.

[0144] In further embodiments, said pathological condition is chosen from
hereditary hemochromatosis and porphyria cutanea tarda.

[0145] In further embodiments, said pathological condition is diabetes.

[0146] In further embodiments, said pathological condition is an acquired
disease that results in excess dietary iron absorption.

[0147] In further embodiments, said pathological condition is a liver
disease.

[0148] In further embodiments, said disease is hepatitis.

[0149] In further embodiments, said pathological condition is lanthanide
or actinide overload.

[0150] In further embodiments, the therapeutically effective amount of a
salt or polymorph thereof as disclosed herein that induces the bodily
excretion of iron or other trivalent metal is greater than 0.2 mg/kg/d in
the subject.

[0151] In further embodiments, the therapeutically effective amount of a
salt or polymorph thereof as disclosed herein can be given at a dose of
at least 10 mg/kg/d without clinically apparent toxic effects on the
kidney, bone marrow, thymus, liver, spleen, heart or adrenal glands.

[0152] As used herein, the terms below have the meanings indicated.

[0153] When ranges of values are disclosed, and the notation "from n1
. . . to n2" is used, where n1 and n2 are the numbers,
then unless otherwise specified, this notation is intended to include the
numbers themselves and the range between them. This range may be integral
or continuous between and including the end values. By way of example,
the range "from 2 to 6 carbons" is intended to include two, three, four,
five, and six carbons, since carbons come in integer units. Compare, by
way of example, the range "from 1 to 3 μM (micromolar)," which is
intended to include 1 μM, 3 μM, and everything in between to any
number of significant figures (e.g., 1.255 μM, 2.1 μM, 2.9999
μM, etc.).

[0154] The term "about," as used herein, is intended to qualify the
numerical values which it modifies, denoting such a value as variable
within a margin of error. When no particular margin of error, such as a
standard deviation to a mean value given in a chart or table of data, is
recited, the term "about" should be understood to mean that range which
would encompass the recited value and the range which would be included
by rounding up or down to that figure as well, taking into account
significant figures.

[0155] The term "acyl," as used herein, alone or in combination, refers to
a carbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl,
heterocycle, or any other moiety were the atom attached to the carbonyl
is carbon. An "acetyl" group refers to a --C(O)CH3 group. An
"alkylcarbonyl" or "alkanoyl" group refers to an alkyl group attached to
the parent molecular moiety through a carbonyl group. Examples of such
groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups
include formyl, alkanoyl and aroyl.

[0156] The term "alkenyl," as used herein, alone or in combination, refers
to a straight-chain or branched-chain hydrocarbon group having one or
more double bonds and containing from 2 to 20 carbon atoms. In certain
embodiments, said alkenyl will comprise from 2 to 6 carbon atoms. The
term "alkenylene" refers to a carbon-carbon double bond system attached
at two or more positions such as ethenylene [(--CH═CH--),(--C::C--)].
Examples of suitable alkenyl groups include ethenyl, propenyl,
2-methylpropenyl, 1,4-butadienyl and the like. Unless otherwise
specified, the term "alkenyl" may include "alkenylene" groups.

[0157] The term "alkoxy," as used herein, alone or in combination, refers
to an alkyl ether group, wherein the term alkyl is as defined below.
Examples of suitable alkyl ether groups include methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and
the like.

[0158] The term "alkyl," as used herein, alone or in combination, refers
to a straight-chain or branched-chain alkyl group containing from 1 to 20
carbon atoms. In certain embodiments, said alkyl will comprise from 1 to
10 carbon atoms. In further embodiments, said alkyl will comprise from 1
to 6 carbon atoms. Alkyl groups may be optionally substituted as defined
herein. Examples of alkyl groups include methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,
hexyl, octyl, noyl and the like. The term "alkylene," as used herein,
alone or in combination, refers to a saturated aliphatic group derived
from a straight or branched chain saturated hydrocarbon attached at two
or more positions, such as methylene (--CH2--). Unless otherwise
specified, the term "alkyl" may include "alkylene" groups.

[0159] The term "alkylamino," as used herein, alone or in combination,
refers to an alkyl group attached to the parent molecular moiety through
an amino group. Suitable alkylamino groups may be mono- or dialkylated,
forming groups such as, for example, N-methylamino, N-ethylamino,
N,N-dimethylamino, N,N-ethylmethylamino and the like.

[0160] The term "alkynyl," as used herein, alone or in combination, refers
to a straight-chain or branched chain hydrocarbon group having one or
more triple bonds and containing from 2 to 20 carbon atoms. In certain
embodiments, said alkynyl comprises from 2 to 6 carbon atoms. In further
embodiments, said alkynyl comprises from 2 to 4 carbon atoms. The term
"alkynylene" refers to a carbon-carbon triple bond attached at two
positions such as ethynylene (--C:::C--, --CC--). Examples of alkynyl
groups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl,
butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like.
Unless otherwise specified, the term "alkynyl" may include "alkynylene"
groups.

[0161] The terms "amido" and "carbamoyl," as used herein, alone or in
combination, refer to an amino group as described below attached to the
parent molecular moiety through a carbonyl group, or vice versa. The term
"C-amido" as used herein, alone or in combination, refers to a
--C(═O)--NR2 group with R as defined herein. The term "N-amido"
as used herein, alone or in combination, refers to a RC(═O)NH--
group, with R as defined herein. The term "acylamino" as used herein,
alone or in combination, embraces an acyl group attached to the parent
moiety through an amino group. An example of an "acylamino" group is
acetylamino (CH3C(O)NH--).

[0162] The term "amino," as used herein, alone or in combination, refers
to NRR', wherein R and R' are independently chosen from hydrogen, alkyl,
acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl,
any of which may themselves be optionally substituted. Additionally, R
and R' may combine to form heterocycloalkyl, either of which may be
optionally substituted.

[0163] The term "aryl," as used herein, alone or in combination, means a
carbocyclic aromatic system containing one, two or three rings wherein
such polycyclic ring systems are fused together. The term "aryl" embraces
aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl.

[0164] The terms "benzo" and "benz," as used herein, alone or in
combination, refer to the divalent group C6H4═ derived from
benzene. Examples include benzothiophene and benzimidazole.

[0165] The term "carbonyl," as used herein, when alone includes formyl
[--C(O)H] and in combination is a --C(O)-- group.

[0166] The term "carboxyl" or "carboxy," as used herein, refers to
--C(O)OH or the corresponding "carboxylate" anion, such as is in a
carboxylic acid salt. An "O-carboxy" group refers to a RC(O)O-- group,
where R is as defined herein. A "C-carboxy" group refers to a --C(O)OR
groups where R is as defined herein.

[0167] The term "cyano," as used herein, alone or in combination, refers
to --CN.

[0168] The term "cycloalkyl," or, alternatively, "carbocycle," as used
herein, alone or in combination, refers to a saturated or partially
saturated monocyclic, bicyclic or tricyclic alkyl group wherein each
cyclic moiety contains from 3 to 12 carbon atom ring members and which
may optionally be a benzo fused ring system which is optionally
substituted as defined herein. In certain embodiments, said cycloalkyl
will comprise from 5 to 7 carbon atoms. Examples of such cycloalkyl
groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl,
2,3-dihydro-1H-indenyl, adamantyl and the like. "Bicyclic" and
"tricyclic" as used herein are intended to include both fused ring
systems, such as decahydronaphthalene, octahydronaphthalene as well as
the multicyclic (multicentered) saturated or partially unsaturated type.
The latter type of isomer is exemplified in general by,
bicyclo[1,1,1]pentane, camphor, adamantane, and bicyclo[3,2,1]octane.

[0169] The term "ester," as used herein, alone or in combination, refers
to a carboxy group bridging two moieties linked at carbon atoms.

[0170] The term "ether," as used herein, alone or in combination, refers
to an oxy group bridging two moieties linked at carbon atoms.

[0171] The term "halo," or "halogen," as used herein, alone or in
combination, refers to fluorine, chlorine, bromine, or iodine.

[0172] The term "haloalkoxy," as used herein, alone or in combination,
refers to a haloalkyl group attached to the parent molecular moiety
through an oxygen atom.

[0173] The term "haloalkyl," as used herein, alone or in combination,
refers to an alkyl group having the meaning as defined above wherein one
or more hydrogens are replaced with a halogen. Specifically embraced are
monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. A monohaloalkyl
group, for one example, may have an iodo, bromo, chloro or fluoro atom
within the group. Dihalo and polyhaloalkyl groups may have two or more of
the same halo atoms or a combination of different halo groups. Examples
of haloalkyl groups include fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,
dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and
dichloropropyl. "Haloalkylene" refers to a haloalkyl group attached at
two or more positions. Examples include fluoromethylene (--CFH--),
difluoromethylene (--CF2--), chloromethylene (--CHCl--) and the
like.

[0174] The term "heteroalkyl," as used herein, alone or in combination,
refers to a stable straight or branched chain, or cyclic hydrocarbon
group, or combinations thereof, fully saturated or containing from 1 to 3
degrees of unsaturation, consisting of the stated number of carbon atoms
and from one to three heteroatoms chosen from O, N, and S, and wherein
the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen
heteroatom may optionally be quaternized. The heteroatom(s) O, N and S
may be placed at any interior position of the heteroalkyl group. Up to
two heteroatoms may be consecutive, such as, for example,
--CH2--NH--OCH3.

[0176] The terms "heterocycloalkyl" and, interchangeably, "heterocycle,"
as used herein, alone or in combination, each refer to a saturated,
partially unsaturated, or fully unsaturated monocyclic, bicyclic, or
tricyclic heterocyclic group containing at least one heteroatom as a ring
member, wherein each said heteroatom may be independently chosen from
nitrogen, oxygen, and sulfur In certain embodiments, said
heterocycloalkyl will comprise from 1 to 4 heteroatoms as ring members.
In further embodiments, said heterocycloalkyl will comprise from 1 to 2
heteroatoms as ring members. In certain embodiments, said
heterocycloalkyl will comprise from 3 to 8 ring members in each ring. In
further embodiments, said heterocycloalkyl will comprise from 3 to 7 ring
members in each ring. In yet further embodiments, said heterocycloalkyl
will comprise from 5 to 6 ring members in each ring. "Heterocycloalkyl"
and "heterocycle" are intended to include sulfones, sulfoxides, N-oxides
of tertiary nitrogen ring members, and carbocyclic fused and benzo fused
ring systems; additionally, both terms also include systems where a
heterocycle ring is fused to an aryl group, as defined herein, or an
additional heterocycle group. Examples of heterocycle groups include
aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl,
dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl,
dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl,
dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl,
isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl,
tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. The
heterocycle groups may be optionally substituted unless specifically
prohibited.

[0177] The term "hydroxy," as used herein, alone or in combination, refers
to --OH.

[0178] The term "hydroxyalkyl," as used herein, alone or in combination,
refers to a hydroxy group attached to the parent molecular moiety through
an alkyl group.

[0179] The phrase "in the main chain" refers to the longest contiguous or
adjacent chain of carbon atoms starting at the point of attachment of a
group to the compounds of any one of the formulas disclosed herein.

[0180] The term "lower," as used herein, alone or in a combination, where
not otherwise specifically defined, means containing from 1 to and
including 6 carbon atoms.

[0181] The terms "oxy" or "oxa," as used herein, alone or in combination,
refer to --O--.

[0182] The term "oxo," as used herein, alone or in combination, refers to
═O.

[0183] The term "perhaloalkoxy" refers to an alkoxy group where all of the
hydrogen atoms are replaced by halogen atoms.

[0184] The term "perhaloalkyl" as used herein, alone or in combination,
refers to an alkyl group where all of the hydrogen atoms are replaced by
halogen atoms.

[0185] The terms "thia" and "thio," as used herein, alone or in
combination, refer to a --S-- group or an ether wherein the oxygen is
replaced with sulfur. The oxidized derivatives of the thio group, namely
sulfinyl and sulfonyl, are included in the definition of thia and thio.

[0186] Any definition herein may be used in combination with any other
definition to describe a composite structural group. By convention, the
trailing element of any such definition is that which attaches to the
parent moiety. For example, the composite group alkylamido would
represent an alkyl group attached to the parent molecule through an amido
group, and the term alkoxyalkyl would represent an alkoxy group attached
to the parent molecule through an alkyl group.

[0187] When a group is defined to be "null," what is meant is that said
group is absent.

[0188] The term "optionally substituted" means the anteceding group may be
substituted or unsubstituted. When substituted, the substituents of an
"optionally substituted" group may include, without limitation, one or
more substituents independently selected from the following groups or a
particular designated set of groups, alone or in combination: lower
alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl,
lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower
haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl,
phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower
acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester,
lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower
alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower
haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic
acid, trisubstituted silyl, N3, SH, SCH3, C(O)CH3,
CO2CH3, CO2H, pyridinyl, thiophene, furanyl, lower
carbamate, and lower urea. Two substituents may be joined together to
form a fused five-, six-, or seven-membered carbocyclic or heterocyclic
ring consisting of zero to three heteroatoms, for example forming
methylenedioxy or ethylenedioxy. An optionally substituted group may be
unsubstituted (e.g., --CH2CH3), fully substituted (e.g.,
--CF2CF3), monosubstituted (e.g., --CH2CH2F) or
substituted at a level anywhere in-between fully substituted and
monosubstituted (e.g., --CH2CF3). Where substituents are
recited without qualification as to substitution, both substituted and
unsubstituted forms are encompassed. Where a substituent is qualified as
"substituted," the substituted form is specifically intended.
Additionally, different sets of optional substituents to a particular
moiety may be defined as needed; in these cases, the optional
substitution will be as defined, often immediately following the phrase,
"optionally substituted with."

[0189] The term Ror the term R', appearing by itself and without a number
designation, unless otherwise defined, refers to a moiety chosen from
hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and
heterocycloalkyl, any of which may be optionally substituted. Such R and
R' groups should be understood to be optionally substituted as defined
herein. Whether an R group has a number designation or not, every R
group, including R, R' and Rn where n=(1, 2, 3, . . . n), every
substituent, and every term should be understood to be independent of
every other in terms of selection from a group. Should any variable,
substituent, or term (e.g. aryl, heterocycle, R, etc.) occur more than
one time in a formula or generic structure, its definition at each
occurrence is independent of the definition at every other occurrence.
Those of skill in the art will further recognize that certain groups may
be attached to a parent molecule or may occupy a position in a chain of
elements from either end as written. Thus, by way of example only, an
unsymmetrical group such as --C(O)N(R)-- may be attached to the parent
moiety at either the carbon or the nitrogen.

[0190] Asymmetric centers exist in the compounds disclosed herein. These
centers are designated by the symbols "R" or "S," depending on the
configuration of substituents around the chiral carbon atom. It should be
understood that the invention encompasses all stereochemical isomeric
forms, including diastereomeric, enantiomeric, and epimeric forms, as
well as d-isomers and 1-isomers, and mixtures thereof. Individual
stereoisomers of compounds can be prepared synthetically from
commercially available starting materials which contain chiral centers or
by preparation of mixtures of enantiomeric products followed by
separation such as conversion to a mixture of diastereomers followed by
separation or recrystallization, chromatographic techniques, direct
separation of enantiomers on chiral chromatographic columns, or any other
appropriate method known in the art. Starting compounds of particular
stereochemistry are either commercially available or can be made and
resolved by techniques known in the art. Additionally, the compounds
disclosed herein may exist as geometric isomers. The present invention
includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z)
isomers as well as the appropriate mixtures thereof. Additionally,
compounds may exist as tautomers; all tautomeric isomers are provided by
this invention. Additionally, the compounds disclosed herein can exist in
unsolvated as well as solvated forms with pharmaceutically acceptable
solvents such as water, ethanol, and the like. In general, the solvated
forms are considered equivalent to the unsolvated forms.

[0191] The term "bond" refers to a covalent linkage between two atoms, or
two moieties when the atoms joined by the bond are considered to be part
of larger substructure. A bond may be single, double, or triple unless
otherwise specified. A dashed line between two atoms in a drawing of a
molecule indicates that an additional bond may be present or absent at
that position.

[0192] The term "disease" as used herein is intended to be generally
synonymous, and is used interchangeably with, the terms "disorder" and
"condition" (as in medical condition), in that all reflect an abnormal
condition of the human or animal body or of one of its parts that impairs
normal functioning, is typically manifested by distinguishing signs and
symptoms, and causes the human or animal to have a reduced duration or
quality of life.

[0193] The term "combination therapy" means the administration of two or
more therapeutic agents to treat a therapeutic condition or disorder
described in the present disclosure. Such administration encompasses
co-administration of these therapeutic agents in a substantially
simultaneous manner, such as in a single capsule having a fixed ratio of
active ingredients or in multiple, separate capsules for each active
ingredient. In addition, such administration also encompasses use of each
type of therapeutic agent in a sequential manner. In either case, the
treatment regimen will provide beneficial effects of the drug combination
in treating the conditions or disorders described herein.

[0194] The phrase "therapeutically effective" is intended to qualify the
amount of active ingredients used in the treatment of a disease or
disorder. This amount will achieve the goal of reducing or eliminating
the said disease or disorder.

[0195] The term "chelation" as used herein means to coordinate (as in a
metal ion) with and inactivate. Chelation also includes decorporation, a
term which itself encompasses chelation and excretion.

[0196] The term "iron-clearing efficiency (ICE)" as used herein refers to
the efficaciousness of a given concentration of chelator in clearing iron
from the body or one of its organs or parts. Efficaciousness in turn
concerns quantity of iron removed from a target system (which may be a
whole body, an organ, or other) in a unit of time. Chelators are needed
for three clinical situations: for acute iron toxicity from ingestion or
infusion of iron; to reduce total body iron secondary to transfusion or
excess iron absorption; for maintenance of iron balance after total body
iron has been satisfactorily reduces and only daily dietary iron needs to
be excreted. In practical terms, therefore, for chronic iron overload
secondary to transfusion, the recommendation is that between 0.3 and 0.5
mg Fe/kg body weight of the patient per day need be excreted. For the
maintenance treatment, 0.25-1 mg/kg/d is sufficient.

[0197] The term "therapeutically acceptable" refers to those compounds (or
salts, polymorphs, prodrugs, tautomers, zwitterionic forms, etc.) which
are suitable for use in contact with the tissues of patients without
undue toxicity, irritation, and allergic response, are commensurate with
a reasonable benefit/risk ratio, and are effective for their intended
use.

[0198] As used herein, reference to "treatment" of a patient is intended
to include prophylaxis. The term "patient" means all mammals including
humans. Examples of patients include humans, cows, dogs, cats, goats,
sheep, pigs, and rabbits. Preferably, the patient is a human.

[0199] The term "prodrug" refers to a compound that is made more active in
vivo. Certain compounds disclosed herein may also exist as prodrugs, as
described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry,
Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M.
Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds
described herein are structurally modified forms of the compound that
readily undergo chemical changes under physiological conditions to
provide the compound. Additionally, prodrugs can be converted to the
compound by chemical or biochemical methods in an ex vivo environment.
For example, prodrugs can be slowly converted to a compound when placed
in a transdermal patch reservoir with a suitable enzyme or chemical
reagent. Prodrugs are often useful because, in some situations, they may
be easier to administer than the compound, or parent drug. They may, for
instance, be bioavailable by oral administration whereas the parent drug
is not. The prodrug may also have improved solubility in pharmaceutical
compositions over the parent drug. A wide variety of prodrug derivatives
are known in the art, such as those that rely on hydrolytic cleavage or
oxidative activation of the prodrug. An example, without limitation, of a
prodrug would be a compound which is administered as an ester (the
"prodrug"), but then is metabolically hydrolyzed to the carboxylic acid,
the active entity. Additional examples include peptidyl derivatives of a
compound.

[0200] The compounds disclosed herein can exist as therapeutically
acceptable salts. Such salts will normally be pharmaceutically
acceptable. However, salts of non-pharmaceutically acceptable salts may
be of utility in the preparation and purification of the compound in
question. Basic addition salts may also be formed and be pharmaceutically
acceptable. For a more complete discussion of the preparation and
selection of salts, refer to Pharmaceutical Salts: Properties, Selection,
and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

[0201] The term "therapeutically acceptable salt," as used herein,
represents salts or zwitterionic forms of the compounds disclosed herein
which are water or oil-soluble or dispersible and therapeutically
acceptable as defined herein. The salts can be prepared during the final
isolation and purification of the compounds or separately by reacting the
appropriate compound in the form of the free base with a suitable acid.
Representative acid addition salts include acetate, adipate, alginate,
L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate,
butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate,
fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate,
heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate,
malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate,
naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,
pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate,
picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate,
tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate,
glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and
undecanoate. Also, basic groups in the compounds disclosed herein can be
quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides,
and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl,
lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl
and phenethyl bromides. Examples of acids which can be employed to form
therapeutically acceptable addition salts include inorganic acids such as
hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids
such as oxalic, maleic, succinic, and citric. Salts can also be formed by
coordination of the compounds with an alkali metal or alkaline earth ion.
Hence, the present invention contemplates sodium, potassium, magnesium,
zinc, and calcium salts of the compounds disclosed herein, and the like.

[0202] Basic addition salts can be prepared during the final isolation and
purification of the compounds, often by reacting a carboxy group with a
suitable base such as the hydroxide, carbonate, or bicarbonate of a metal
cation or with ammonia or an organic primary, secondary, or tertiary
amine. The cations of therapeutically acceptable salts include lithium,
sodium (e.g., NaOH), potassium (e.g., KOH), calcium (including
Ca(OH)2), magnesium (including Mg(OH)2 and magnesium acetate),
zinc, (including Zn(OH)2 and zinc acetate) and aluminum, as well as
nontoxic quaternary amine cations such as ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, diethylamine, ethylamine, tributylamine, pyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,
dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,
1-ephenamine, and N,N-dibenzylethylenediamine. Other representative
organic amines useful for the formation of base addition salts include
ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine,
choline hydroxide, hydroxyethyl morpholine, hydroxyethyl pyrrolidone,
imidazole, n-methyl-d-glucamine, N,N'-dibenzylethylenediamine,
N,N'-diethylethanolamine, N,N'-dimethylethanolamine, triethanolamine, and
tromethamine. Basic amino acids such as 1-glycine and 1-arginine, and
amino acids which may be zwitterionic at neutral pH, such as betaine
(N,N,N-trimethylglycine) are also contemplated.

[0204] Salts disclosed herein may combine in 1:1 molar ratios, and in fact
this is often how they are initially synthesized. However, it will be
recognized by one of skill in the art that the stoichiometry of one ion
in a salt to the other may be otherwise. Salts shown herein may be, for
the sake of convenience in notation, shown in a 1:1 ratio; all possible
stoichiometric arrangements are encompassed by the scope of the present
invention.

[0205] When the phrase "X is a counterion" is used in structural formulas
I, II, III, IV V, and VI herein, and neither the compound nor the
counterion is drawn showing explicit ionic character, such ionic
character may be inferred and a corresponding charges on each moiety be
assumed to be present or absent. For example, if X is a monovalent cation
such as Mg(OH).sup.+, it may be inferred that the coupled compound has
lost a proton to form an ionic bond with X, despite Formula I being drawn
to explicitly show all protons in place. Similarly, when X is an anion,
the coupled compound takes on cationic character. The notation is left
intentionally ambiguous as to placement and ratios of charges since
without extensive physical characterization, such as X-ray crystal
diffraction, it is often impossible to know with certainty where on a
compound a counterion has bound. Additionally, counterions and compounds
may combine in uneven molar ratios to form solid salts.

[0206] The terms, "polymorphs" and "polymorphic forms" and related terms
herein refer to crystal forms of the same molecule, and different
polymorphs may have different physical properties such as, for example,
melting temperatures, heats of fusion, solubilities, dissolution rates
and/or vibrational spectra as a result of the arrangement or conformation
of the molecules in the crystal lattice. The differences in physical
properties exhibited by polymorphs affect pharmaceutical parameters such
as storage stability, compressibility and density (important in
formulation and product manufacturing), and dissolution rates (an
important factor in bioavailability). Differences in stability can result
from changes in chemical reactivity (e.g. differential oxidation, such
that a dosage form discolors more rapidly when comprised of one polymorph
than when comprised of another polymorph) or mechanical changes (e.g.
tablets crumble on storage as a kinetically favored polymorph converts to
thermodynamically more stable polymorph) or both (e.g., tablets of one
polymorph are more susceptible to breakdown at high humidity). As a
result of solubility/dissolution differences, in the extreme case, some
polymorphic transitions may result in lack of potency or, at the other
extreme, toxicity. In addition, the physical properties of the crystal
may be important in processing, for example, one polymorph might be more
likely to form solvates or might be difficult to filter and wash free of
impurities (i.e., particle shape and size distribution might be different
between polymorphs).

[0207] Described herein are various polymorphic forms such as Form A, Form
B, form C, amorphous, and the like. These terms (Form A, Form B, etc. as
the case may be) encompass polymorphs that are substantially similar to
those described herein. In this context, "substantially similar" means
that one of skill in the art would recognize the polymorphs differing
insignificantly from those polymorphs as physically characterized herein,
or those polymorphs having one or more properties described herein. By
way of example, a polymorph encompassed by the term Form A could have an
X-ray powder diffraction (XRPD) spectrum which is at least 70%, at least
80%, at least 90%, or at least 95% identical to that shown in the XRPD
for Form A. For example, the encompassed polymorph might have at least
80% of the peaks in common with the disclosed Form A (shown in FIG. 7).
Alternatively, if the XRPD spectrum is identified by only a few major
peaks, the encompassed polymorph might have major peaks at least 80%
identical to those shown in an XRPD spectrum. Alternatively, the
encompassed polymorph might have an aqueous solubility which is within 80
to 120% that shown herein.

[0208] Polymorphs of a molecule can be obtained by a number of methods, as
known in the art. Such methods include, but are not limited to, melt
recrystallization, melt cooling, solvent recrystallization, desolvation,
rapid evaporation, rapid cooling, slow cooling, vapor diffusion and
sublimation.

[0210] The term, "solvate," as used herein, refers to a crystal form of a
substance which contains solvent. The term "hydrate" refers to a solvate
wherein the solvent is water.

[0211] The term, "desolvated solvate," as used herein, refers to a crystal
form of a substance which can only be made by removing the solvent from a
solvate.

[0212] The term "amorphous form," as used herein, refers to a
noncrystalline form of a substance.

[0213] The term "solubility" is generally intended to be synonymous with
the term "aqueous solubility," and refers to the ability, and the degree
of the ability, of a compound to dissolve in water or an aqueous solvent
or buffer, as might be found under physiological conditions. Aqueous
solubility is, in and of itself, a useful quantitative measure, but it
has additional utility as a correlate and predictor, with some
limitations which will be clear to those of skill in the art, of oral
bioavailability. In practice, a soluble compound is generally desirable,
and the more soluble, the better. There are notable exceptions; for
example, certain compounds intended to be administered as depot
injections, if stable over time, may actually benefit from low
solubility, as this may assist in slow release from the injection site
into the plasma. Solubility is typically reported in mg/mL, but other
measures, such as g/g, may be used. Solubilities typically deemed
acceptable may range from 1 mg/mL into the hundreds or thousands of
mg/mL.

[0214] Solubility may be measured under varying conditions. For example,
it may be measured under conditions similar to those found in the body,
such as at gastric pH or at physiologic or near-physiologic pH. "Gastric
pH" as used herein means about pH 1. "Near-physiologic pH," as used
herein refers to the typical pH of bodily tissues and fluids, such as
blood and plasma, or cytoplasm, generally about 7.4.

[0215] As used herein, "solid" when referring to a salt form means
relatively solid, at room temperature, and/or containing a substantial
amount of solids. A solid may be amorphous in form and/or be a solvated
solid with some quantity of residual or coordinated of solvent molecules.
A crystalline salt is an example of a solid. By way of example, a wax
could be considered a solid, whereas an oil would not be.

[0216] A "solid composition" as used herein includes a salt of a compound,
or a polymorph or amorphous solid form thereof.

[0217] While it may be possible for the compounds, salts and polymorphs
disclosed herein to be administered as the raw chemical, it is also
possible to present them as a pharmaceutical formulation. Accordingly,
provided herein are pharmaceutical formulations which comprise one or
more of certain compounds, salts and polymorphs disclosed herein, or one
or more pharmaceutically acceptable salts, esters, prodrugs, amides, or
solvates thereof, together with one or more pharmaceutically acceptable
carriers thereof and optionally one or more other therapeutic
ingredients. The carrier(s) must be "acceptable" in the sense of being
compatible with the other ingredients of the formulation and not
deleterious to the recipient thereof. Proper formulation is dependent
upon the route of administration chosen. Any of the well-known
techniques, carriers, and excipients may be used as suitable and as
understood in the art; e.g., in Remington's Pharmaceutical Sciences. The
pharmaceutical compositions disclosed herein may be manufactured in any
manner known in the art, e.g., by means of conventional mixing,
dissolving, granulating, dragee-making, levigating, emulsifying,
encapsulating, entrapping or compression processes.

[0218] The formulations include those suitable for oral, parenteral
(including subcutaneous, intradermal, intramuscular, intravenous,
intraarticular, and intramedullary), intraperitoneal, transmucosal,
transdermal, intranasal, rectal and topical (including dermal, buccal,
sublingual and intraocular) administration although the most suitable
route may depend upon for example the condition and disorder of the
recipient. The formulations may conveniently be presented in unit dosage
form and may be prepared by any of the methods well known in the art of
pharmacy. Typically, these methods include the step of bringing into
association a compound or a pharmaceutically acceptable salt, ester,
amide, prodrug or solvate thereof ("active ingredient") with the carrier
which constitutes one or more accessory ingredients. In general, the
formulations are prepared by uniformly and intimately bringing into
association the active ingredient with liquid carriers or finely divided
solid carriers or both and then, if necessary, shaping the product into
the desired formulation.

[0219] Formulations of the compounds, salts and polymorphs disclosed
herein suitable for oral administration may be presented as discrete
units such as capsules, cachets or tablets each containing a
predetermined amount of the active ingredient; as a powder or granules;
as a solution or a suspension in an aqueous liquid or a non-aqueous
liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid
emulsion. The active ingredient may also be presented as a bolus,
electuary or paste.

[0220] Pharmaceutical preparations which can be used orally include
tablets, push-fit capsules made of gelatin, as well as soft, sealed
capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
Tablets may be made by compression or molding, optionally with one or
more accessory ingredients. Compressed tablets may be prepared by
compressing in a suitable machine the active ingredient in a free-flowing
form such as a powder or granules, optionally mixed with binders, inert
diluents, or lubricating, surface active or dispersing agents. Molded
tablets may be made by molding in a suitable machine a mixture of the
powdered compound moistened with an inert liquid diluent. The tablets may
optionally be coated or scored and may be formulated so as to provide
slow or controlled release of the active ingredient therein. All
formulations for oral administration should be in dosages suitable for
such administration. The push-fit capsules can contain the active
ingredients in admixture with filler such as lactose, binders such as
starches, and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the active compounds, salts
and polymorphs may be dissolved or suspended in suitable liquids, such as
fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers may be added. Dragee cores are provided with suitable
coatings. For this purpose, concentrated sugar solutions may be used,
which may optionally contain gum arabic, talc, polyvinyl pyrrolidone,
carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer
solutions, and suitable organic solvents or solvent mixtures. Dyestuffs
or pigments may be added to the tablets or dragee coatings for
identification or to characterize different combinations of active
compound doses.

[0221] The compounds, salts and polymorphs may be formulated for
parenteral administration by injection, e.g., by bolus injection or
continuous infusion. Formulations for injection may be presented in unit
dosage form, e.g., in ampoules or in multi-dose containers, with an added
preservative. The compositions may take such forms as suspensions,
solutions or emulsions in oily or aqueous vehicles, and may contain
formulatory agents such as suspending, stabilizing and/or dispersing
agents. The formulations may be presented in unit-dose or multi-dose
containers, for example sealed ampoules and vials, and may be stored in
powder form or in a freeze-dried (lyophilized) condition requiring only
the addition of the sterile liquid carrier, for example, saline or
sterile pyrogen-free water, immediately prior to use. Extemporaneous
injection solutions and suspensions may be prepared from sterile powders,
granules and tablets of the kind previously described.

[0222] Formulations for parenteral administration include aqueous and
non-aqueous (oily) sterile injection solutions of the active compounds,
salts and polymorphs which may contain antioxidants, buffers,
bacteriostats and solutes which render the formulation isotonic with the
blood of the intended recipient; and aqueous and non-aqueous sterile
suspensions which may include suspending agents and thickening agents.
Suitable lipophilic solvents or vehicles include fatty oils such as
sesame oil, or synthetic fatty acid esters, such as ethyl oleate or
triglycerides, or liposomes. Aqueous injection suspensions may contain
substances which increase the viscosity of the suspension, such as sodium
carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension
may also contain suitable stabilizers or agents which increase the
solubility of the compounds, salts and polymorphs to allow for the
preparation of highly concentrated solutions.

[0223] In addition to the formulations described previously, a compound,
salt, or polymorph as disclosed herein may also be formulated as a depot
preparation. Such long acting formulations may be administered by
implantation (for example subcutaneously or intramuscularly) or by
intramuscular injection. Thus, for example, the compounds, salts and
polymorphs may be formulated with suitable polymeric or hydrophobic
materials (for example as an emulsion in an acceptable oil) or ion
exchange resins, or as sparingly soluble derivatives, for example, as a
sparingly soluble salt.

[0224] For buccal or sublingual administration, the compositions may take
the form of tablets, lozenges, pastilles, or gels formulated in
conventional manner. Such compositions may comprise the active ingredient
in a flavored basis such as sucrose and acacia or tragacanth.

[0225] The compounds, salts and polymorphs may also be formulated in
rectal compositions such as suppositories or retention enemas, e.g.,
containing conventional suppository bases such as cocoa butter,
polyethylene glycol, or other glycerides.

[0226] Certain compounds, salts and polymorphs disclosed herein may be
administered topically, that is by non-systemic administration. This
includes the application of a compound disclosed herein externally to the
epidermis or the buccal cavity and the instillation of such a compound
into the ear, eye and nose, such that the compound does not significantly
enter the blood stream. In contrast, systemic administration refers to
oral, intravenous, intraperitoneal and intramuscular administration.

[0227] Formulations suitable for topical administration include liquid or
semi-liquid preparations suitable for penetration through the skin to the
site of inflammation such as gels, liniments, lotions, creams, ointments
or pastes, and drops suitable for administration to the eye, ear or nose.
The active ingredient for topical administration may comprise, for
example, from 0.001% to 10% w/w (by weight) of the formulation. In
certain embodiments, the active ingredient may comprise as much as 10%
w/w. In other embodiments, it may comprise less than 5% w/w. In certain
embodiments, the active ingredient may comprise from 2% w/w to 5% w/w. In
other embodiments, it may comprise from 0.1% to 1% w/w of the
formulation.

[0228] For administration by inhalation, compounds, salts and polymorphs
may be conveniently delivered from an insufflator, nebulizer pressurized
packs or other convenient means of delivering an aerosol spray.
Pressurized packs may comprise a suitable propellant such as
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the
case of a pressurized aerosol, the dosage unit may be determined by
providing a valve to deliver a metered amount. Alternatively, for
administration by inhalation or insufflation, the compounds, salts and
polymorphs disclosed herein may take the form of a dry powder
composition, for example a powder mix of the compound and a suitable
powder base such as lactose or starch. The powder composition may be
presented in unit dosage form, in for example, capsules, cartridges,
gelatin or blister packs from which the powder may be administered with
the aid of an inhalator or insufflator.

[0229] Intranasal delivery, in particular, may be useful for delivering
compounds to the CNS. It had been shown that intranasal drug
administration is a noninvasive method of bypassing the blood-brain
barrier (BBB) to deliver neurotrophins and other therapeutic agents to
the brain and spinal cord. Delivery from the nose to the CNS occurs
within minutes along both the olfactory and trigeminal neural pathways.
Intranasal delivery occurs by an extracellular route and does not require
that drugs bind to any receptor or undergo axonal transport. Intranasal
delivery also targets the nasal associated lymphatic tissues (NALT) and
deep cervical lymph nodes. In addition, intranasally administered
therapeutics are observed at high levels in the blood vessel walls and
perivascular spaces of the cerebrovasculature. Using this intranasal
method in animal models, researchers have successfully reduced stroke
damage, reversed Alzheimer's neurodegeneration, reduced anxiety, improved
memory, stimulated cerebral neurogenesis, and treated brain tumors. In
humans, intranasal insulin has been shown to improve memory in normal
adults and patients with Alzheimer's disease. Hanson L R and Frey W H,
2nd, J Neuroimmune Pharmacol. 2007 March; 2(1):81-6. Epub 2006 Sep.
15.

[0230] Preferred unit dosage formulations are those containing an
effective dose, as herein below recited, or an appropriate fraction
thereof, of the active ingredient.

[0231] It should be understood that in addition to the ingredients
particularly mentioned above, the formulations described above may
include other agents conventional in the art having regard to the type of
formulation in question, for example those suitable for oral
administration may include flavoring agents.

[0232] Compounds, salts and polymorphs may be administered orally or via
injection at a dose of from 0.1 to 500 mg/kg per day. The dose range for
adult humans is generally from 5 mg to 2 g/day. Tablets or other forms of
presentation provided in discrete units may conveniently contain an
amount of one or more compounds, salts and polymorphs which is effective
at such dosage or as a multiple of the same, for instance, units
containing 5 mg to 500 mg, usually around 10 mg to 200 mg.

[0233] The amount of active ingredient that may be combined with the
carrier materials to produce a single dosage form will vary depending
upon the host treated and the particular mode of administration.

[0234] The compounds, salts and polymorphs can be administered in various
modes, e.g. orally, topically, or by injection. The precise amount of
compound administered to a patient will be the responsibility of the
attendant physician. The specific dose level for any particular patient
will depend upon a variety of factors including the activity of the
specific compound employed, the age, body weight, general health, sex,
diets, time of administration, route of administration, rate of
excretion, drug combination, the precise disorder being treated, and the
severity of the indication or condition being treated. Also, the route of
administration may vary depending on the condition and its severity.

[0235] In certain instances, it may be appropriate to administer at least
one of the compounds, salts and polymorphs described herein (or a
pharmaceutically acceptable salt, ester, or prodrug thereof) in
combination with another therapeutic agent. By way of example only, if
one of the side effects experienced by a patient upon receiving one of
the compounds herein for the treatment of actinide poisoning is depletion
of essential trace minerals required by the body for proper functioning,
then it may be appropriate to administer a strong chelating agent in
combination with supplements of essential trace minerals required by the
body for proper functioning, for example zinc and magnesium, to replace
those which will inadvertently be lost to chelation therapy. Or, by way
of example only, the therapeutic effectiveness of one of the compounds
described herein may be enhanced by administration of an adjuvant (i.e.,
by itself the adjuvant may only have minimal therapeutic benefit, but in
combination with another therapeutic agent, the overall therapeutic
benefit to the patient is enhanced). Or, by way of example only, the
benefit of experienced by a patient may be increased by administering one
of the compounds described herein with another therapeutic agent (which
also includes a therapeutic regimen) that also has therapeutic benefit.
By way of example only, in a treatment for thalassemia involving
administration of one of the compounds described herein, increased
therapeutic benefit may result by also providing the patient with another
therapeutic agent for thalassemia, for example deferoxamine. In any case,
regardless of the disease, disorder or condition being treated, the
overall benefit experienced by the patient may simply be additive of the
two therapeutic agents or the patient may experience a synergistic
benefit.

[0237] In any case, the multiple therapeutic agents (at least one of which
is a compound disclosed herein) may be administered in any order or even
simultaneously. If simultaneously, the multiple therapeutic agents may be
provided in a single, unified form, or in multiple forms (by way of
example only, either as a single pill or as two separate pills). One of
the therapeutic agents may be given in multiple doses, or both may be
given as multiple doses. If not simultaneous, the timing between the
multiple doses may be any duration of time ranging from a few minutes to
four weeks.

[0238] Thus, in another aspect, certain embodiments provide methods for
treating disorders and symptoms relating to metal toxicity in a human or
animal subject in need of such treatment comprising administering to said
subject an amount of a compound disclosed herein effective to reduce or
prevent said disorder in the subject, in combination with at least one
additional agent for the treatment of said disorder that is known in the
art. In a related aspect, certain embodiments provide therapeutic
compositions comprising at least one compound disclosed herein in
combination with one or more additional agents for the treatment of
disorders and symptoms relating to metal toxicity.

[0239] Specific diseases to be treated by the compounds, compositions, and
methods disclosed herein include iron overload or mal-distribution or
redistribution of iron in the body such as atransferrinemia,
aceruloplasminemia, or Fredreich's ataxia; transfusional iron overload
such as with beta-thalassemia major and intermedia, sickle cell anemia,
Diamond-Blackfan anemia, sideroblastic anemia, chronic hemolytic anemias,
off-therapy leukemias, bone marrow transplant or myelodysplastic
syndrome; a hereditary condition resulting in the excess absorption of
dietary iron such as hereditary hemochromatosis, or porphyria cutanea
tarda; an acquired disease that results in excess dietary iron absorption
such as hepatitis; and other liver diseases; lanthanide or actinide acute
poisoning or chronic overload.

[0240] Besides being useful for human treatment, certain compounds and
formulations disclosed herein may also be useful for veterinary treatment
of companion animals, exotic animals and farm animals, including mammals,
rodents, and the like. More preferred animals include horses, dogs, and
cats.

[0241] All references, patents or applications, U.S. or foreign, cited in
the application are hereby incorporated by reference as if written herein
in their entireties. Where any inconsistencies arise, material literally
disclosed herein controls.

General Synthetic Methods for Preparing Compounds

[0242] Certain compounds from which salts and polymorphs as disclosed
herein may be formed can be synthesized as described in Bergeron, R J et
al., "Design, Synthesis, and Testing of Non-Nephrotoxic
Desazadesferrithiocin Polyether Analogues," J Med. Chem. 2008, 51(13),
3913-23.

[0243] The following methods can be used to practice the present
invention.

were performed manually in typical glassware. Salt screen experiments
were carried out typically using a 1:1 ratio of 4'-(OH)-DADFT-PE or
3'-(OH)-DADFT-PE to salt former. A ratio of 1:2 was occasionally used,
such as when calcium and magnesium hydroxides were utilized as salt
formers. Experiments were conducted by direct mixing of solvent
containing free acid and base. Standard techniques for the formation and
isolation of salts were applied, including but not limited to: solution
in and addition of different solvents at various rates, heating,
stifling, cooling, slow and/or fast evaporation, optionally under N2
atmosphere, elevated and subambient temperature, rotary evaporation,
slurry formation and use of a slurry wheel, isolation and workup of
supernatants, trituration, and filtration. The methods could be applied
to find salts of any compound of Formula I.

[0245] Following isolation, salts were then characterized by one or more
standard techniques including but not limited to x-ray powder diffraction
(XRPD), single crystal x-ray diffraction (SC-XRD or XRD), nuclear
magnetic resonance (NMR), solubility analysis, and stability testing by
moisture sorption/desorption stress analysis and differential scanning
calorimetry (DSC).

[0246] Throughout the experimental protocols, the following abbreviations
may be used. The list below is provided for convenience and is not
intended to be inclusive.

[0247] Solutions were generated at ambient temperature upon mixing
4'-(OH)-DADFT-PE or 3'-(OH)-DADFT-PE with salt former of specified molar
concentration. The solutions were allowed to evaporate to dryness from a
vial either covered with aluminum foil containing pinholes (slow
evaporation, SE) or left open for fast evaporation (FE). If no solids
were formed, additional crystallization techniques were used.

Rotary Evaporation

[0248] Solutions were generated at ambient temperature upon mixing
4'-(OH)-DADFT-PE or 3'-(OH)-DADFT-PE with salt former of specified molar
concentration. The solvents were then removed using a rotary evaporator
(RE) at ambient or elevated temperature. If a film resulted, additional
crystallization techniques were used.

Cooling Experiments

[0249] Solutions or suspensions were generated at ambient or elevated
temperature upon mixing 4'-(OH)-DADFT-PE or 3'-(OH)-DADFT-PE with salt
former of specified molar concentration. Solutions or suspensions
prepared at ambient were warmed up for further treatment. Resulting
mixtures were allowed to cool down to ambient by placing them on an
ambient stifling plate (fast cooling, FC) or turning the heating device
off (slow cooling, SC). Solids formed were isolated by vacuum filtration.
If no solids were collected, additional crystallization techniques were
used.

Vapor Diffusion

[0250] Solutions were generated at ambient temperature upon mixing
4'-(OH)-DADFT-PE or 3'-(OH)-DADFT-PE with salt former of specified molar
concentration. The vial (typically 1 dram) with the sample solution was
placed uncapped in a 20 mL scintillation vial with an appropriate
antisolvent. The 20 ml vial was then capped and the sample left
undisturbed for specified amount of time. If no solids were formed,
additional crystallization techniques were used.

Slurry Experiments

[0251] Slurry experiments were used as an additional crystallization
technique. The solvent was added and the mixture was then agitated in a
sealed vial at ambient. After a given amount of time, the solids were
isolated by vacuum filtration.

Approximate Solubility

[0252] Weighed samples were treated with aliquots of test solvents at room
temperature. Samples were typically sonicated between additions to
facilitate dissolution. Complete dissolution of the test material in each
solvent was determined by visual inspection. Solubility was estimated
based on the total volume of solvent used to provide complete
dissolution. The actual solubility may be greater than the value
calculated due to the incremental addition of solvent and kinetics of
dissolution of the material. The solubility is expressed as "less than"
if dissolution did not occur during the experiment. The solubility is
expressed as "less than" if dissolution occurred after the addition of
first aliquot.

X-Ray Powder Diffraction (XRPD)

[0253] XRPD patterns were collected using an Inel XRG-3000 diffractometer
equipped with a curved position sensitive detector with a 20 range of
120°. An incident beam of Cu Kα radiation (40 kV, 30 mA) was
used to collect data in real time at a resolution of 0.03°
2θ. Prior to the analysis, a silicon standard (NIST SRM 640c) was
analyzed to verify the Si 111 peak position. Samples were prepared for
analysis by packing them into thin-walled glass capillaries. Each
capillary was mounted onto a goniometer head and rotated during data
acquisition. The monochromator slit was set at 5 mm by 160 μm, and the
samples were analyzed for 300 seconds.

[0254] XRPD patterns were collected using a PANalytical X'Pert Pro
diffractometer. An incident beam of Cu Kα radiation was produced
using a ceramic tube with a long, fine-focus source and a nickel filter.
The diffractometer was configured using the symmetric Bragg-Brentano
geometry with a reflection stage and a manually operated spinner. Data
were collected and analyzed using X'Pert Pro Data Collector software (v.
2.2b). Prior to the analysis, a silicon specimen (NIST SRM 640c) was
analyzed to verify the Si 111 peak position. The specimen was prepared as
a thin, circular layer centered on a silicon zero-background substrate.
Anti-scatter slits were used to minimize the background generated by air
scattering. Soller slits were used for the incident and diffracted beams
to minimize axial divergence. Diffraction patterns were collected using a
scanning position-sensitive detector (X'Celerator) located 240 mm from
the specimen.

Differential Scanning calorimetry

[0255] Differential scanning calorimetry (DSC) analyses were performed
using a TA Instruments differential scanning calorimeter Q2000. Each
sample was placed into an aluminum DSC pan, and the weight accurately
recorded. The pan was covered with an inverted lid and crimped. The
sample cell was equilibrated at -30° C. and heated under a
nitrogen purge at a rate of 10° C./min, up to a final temperature
of 250° C. Indium metal was used as the calibration standard.

Thermogravimetric Analysis

[0256] Thermogravimetric (TG) analyses were performed using a TA
Instruments Q5000 and 2950 thermogravimetric analyzers. Each sample was
placed in an aluminum sample pan and inserted into the TG furnace. The
furnace was heated under nitrogen at a rate of 10° C./min, up to a
final temperature of 350° C. Nickel and Alumel were used as the
calibration standards.

Moisture Sorption Analysis

[0257] Moisture sorption/desorption (DVS) data were collected on a VTI
SGA-100 Vapor Sorption Analyzer. Sorption and desorption data were
collected over a range of 5% to 95% relative humidity (RH) at 10% RH
intervals under a nitrogen purge. Samples were not dried prior to
analysis. Equilibrium criteria used for analysis were less than 0.0100%
weight change in 5 minutes, with a maximum equilibration time of 3 hours
if the weight criterion was not met. Data were not corrected for the
initial moisture content of the samples. NaCl and PVP were used as
calibration standards.

Nuclear Magnetic Resonance Spectroscopy (NMR)

[0258] Solution 1H-NMR spectra were acquired at SSCI with a Varian
UNITYINOVA-400 spectrometer. All samples were prepared in deuterated
dimethyl sulfoxide (DMSO). The data acquisition parameters are available
on the first plot of the spectrum for each sample, presented in the data
section.

[0259] The invention is further illustrated by the following examples.

Example 1

Attempts to Produce Salts of (S)-3'-(OH)-DADFT-PE

[0260] The results of an initial screen of salts of a representative
compound, (S)-3'-(OH)-DADFT-PE, are given below in Table 1. Approximately
52 experiments were performed.

formed. Solvent was decanted,
solid dried under N2 stream.
A subsample of above. Solid In progress --
was resuspended in ether.
Placed on a slurry wheel at RT.
Magnesium 27 mg of magnesium acetate Bright yellow Amorphous
acetate was added to 0.25 ml of API solid
(1:1) solution (200 mg/ml) in IPA,
sonicated, resulted in clear
solution. Solvent was
evaporated under N2 stream.
The remaining yellow gel was
resuspended in ether.
Sonicated, bright yellow solid
formed. Solvent was decanted,
solid dried under N2 stream.
KOH 1. Added 2.0 mL API solution Bright yellow Unique
(1:1) in MeOH to base solution in solids, fibrous fan pattern
MeOH (~10 mg base/mL), rosettes (B/E) (Form A)
agitated 16 hours.
2. Added 10 mL ether: no
precipitation.
3. Evaporated solvents under
N2.
4. Redissolved in 1 mL MeOH.
5. Added 10 mL ether: plumes
of intense haze with a few B/E
particles. Added incremental
amounts of ether to a final
volume of 4 mL: stable
turbidity for ~3 h with
dissipation/solution.
6. VSE/FE under N2 for ~4
days: clear, yellow oil.
7. Triturated in ether on rotary
wheel, decanted supernatant,
dried solids with N2.
KOH ~1 eq of KOH was added to In progress --
(1:1) the API solution in ethyl
acetate. Solution turned turbid
after sonication, brown oil
formed in yellow cloudy
solution. Solvent was
evaporated under N2 stream.
Brown oil remained
unchanged. Stirred at RT.
KOH ~1 eq of KOH was added to Light yellow solid In progress
(1:1) the API solution in THF.
Solution turned clear after
sonication. Solvent was
evaporated under N2 stream.
The resulting light yellow film
was resuspended in MTBE,
sonicated, light yellow solid
formed. Solvent was decanted,
the remaining solid was dried
under N2 stream.
KOH ~1 eq of KOH was added to In progress --
(1:1) the API solution in IPA.
Sonicated, resulted in clear
yellow solution. Solvent was
evaporated under N2 stream.
To the resulting yellow film
was added MTBE. Bright
yellow tacky solid formed on
the bottom of the vial. Stirred
at RT.
NaOH API solution in EtOH was Gel, plate-like Amorphous
(1:1) added to aqueous solution of particles, specks, pattern +
base with minimal water, SE, elongate NaCl
RT vac oven 1 day hexagonal plates,
blades (B/E)
NaOH API solution in EtOH was Cloudy yellow --
(1:1) added to aqueous solution of liquid
base with minimal water,
SE/stir. (1)
Sample (1) above was Gummy glass --
precipitated with ether to final (no B/E)
vol. of EtOH/ether (1:40),
refrigerated for 0.5 hour,
decanted liquid, RT dry. (2)
RT slurry on an orbit shaker of Yellow oil --
(2) above.
Solution of (2) above refrig 0.5 Clear yellow --
hour. Kept in refrigerator for solution
42 days.
Film precipitated from (1) Yellow oil on the --
above with heptane to a final bottom of the
vol. of EtOH/heptane (1:50), vial, clear solvent
kept in a freezer for 57 days. phase on top
THF to (1) to a final vol of Clear yellow --
EtOH/THF (1:50), kept in a solution
freezer for 57 days.
Toluene to (1) to a final vol. of Small amount of --
EtOH/toluene (1:50), kept in a oily precipitate in
freezer for 57 days. a clear yellow
solution. A few
birefringent
specks.
NaOH To an API solution in EtOH Yellow oil --
(1:1) was added 1,4-dioxane to a
final vol. of 1:50 (EtOH/1,4-
dioxane), SE in a fume hood.
NaOH To an API solution in EtOH Fine needles in Solid
(1:1) was added ether. Refrigerated dense rosette deliquesced
for 15 days. clusters (B) or passed
through
upon
filtration
EtOH/ether to above, FE under Yellow gel Amorphous
N2.
Base solution to above. Glassy yellow Amorphous
Refrigerated for 15 days. solid
Yellow precipitate on the
bottom of the vial. Solvent
decanted, solid dried under N2
stream.
NaOH 1. Added 2.0 mL API solution Tacky, amber --
(1:1) in MeOH to base solution in film
MeOH (~9 mg base/mL),
mixed on a rotary wheel for 16
hours.
2. Added 10 mL ether: no
precipitation.
3. Evaporated solvents under
N2 to ~1 mL; repeated dilution
with 20 mL ether: let stand
overnight: clear solution with a
few tiny particles (B, E). Let
stand ≧15 h: no change.
4. Evaporated solvents under
N2.
Subjected 3.3 mg of solid from "feather" plumes In progress
above to MeOH vapor stress. (B/E)
Subjected 3.6 mg of solid from Amber gel film In progress
above to ether vapor stress.
NaOH To 0.5 ml of API solution in Birefringent fine --
(1:1) MeOH was added 1N NaOH needles in tacky
in water. Clear solution. FE at gel
RT. The resulting yellow oil (failed to collect)
was dried briefly under N2
stream. Ether was added.
Placed on a slurry wheel at RT
for 13 days. Solvent was
decanted, the remaining gel
was dried under N2. Resulted
in tacky gel.
NaOH To 0.5 ml of API solution in Birefringent Amorphous
(1:1) EtOH was added 1 equivalent specks in
of solid NaOH. Slow yellowish brown
evaporated at RT while solid
stirring. To the resulting turbid
yellow oil was added ether.
Continued to stir at RT for 3
days. Tacky yellowish brown
precipitate attached to the
bottom of the vial. Solvent
was decanted. Ether was
added, yellowish brown solid
formed. Vacuum filtered.
Solid deliquesced on the paper
filter. Small amount of
remaining solid in the vial was
dried under N2 stream.
NaOH To 0.25 ml of API solution in Yellowish brown Amorphous
(1:1) MeOH was added 1 equivalent solid (free-flow
of solid NaOH, resulted in dark powder)
brown solution. The solvent
was evaporated under N2
stream, and the resulting brown
film was suspended in ether.
Yellowish brown solid formed.
The suspension was further
mixed on a slurry wheel at RT
for 1 day. Solvent was
decanted, the remaining solid
was dried under N2 stream.
NaOH To 0.5 ml of API solution in Dark yellowish Amorphous
(1:1) THF was added 1 equivalent of brown solid
solid NaOH, resulted in dark
brown solution. The solvent
was evaporated under N2
stream, and the resulting brown
film was suspended in ether.
Yellowish brown solid formed.
The suspension was further
mixed on a slurry wheel at RT
for 1 day. Solvent was
decanted, the remaining solid
was dried under N2 stream.
NaOH To 0.25 ml of API solution in Light brown solid Amorphous
(1:1) IPA was added 1 equivalent of
solid NaOH, followed by 0.05 ml
of water, resulted in clear
solution. The solvent was
evaporated under N2 stream,
and the resulting yellow film
was suspended in ether. Light
yellow solid formed. Solvent
was decanted, and the
remaining solid was dried
under N2 stream.
NaOH To 0.25 ml of API solution in Bright yellow Amorphous
(1:1) ACN was added 1 equivalent solid
of solid NaOH, followed by
0.05 ml of water, resulted in
clear solution. The solvent was
evaporated under N2 stream,
and the resulting yellow film
was suspended in ether. Tacky
yellow gel formed. The vial
was capped, slurried at RT for
1 day. Clear solvent was
decanted, and the remaining
gel was dried under N2 stream.
NaOH lyophilization of a solution in yellow solids --
(1:1) t-butyl alcohol. (1)
A solution of exposure of (1) to ambient air solids deliquesced --
29.2 mg/mL of (~57% RH) for a few minutes to a yellow oil
NaOH in evaporation of a solution of (1) In progress --
methanol was in toluene
used slurry of (1) in pentane In progress --
slurry of (1) in 1:1 ethyl In progress --
ether:pentane
NaOH 1. Dissolved starting material Tacky, yellow --
(1:1) in ethyl ether, dried with material
A solution of anhydrous sodium sulfate and
29.2 mg/mL of filtered.
NaOH in 2. Added 1 eq. of methanolic
methanol was NaOH and enough methanol to
used the filtrate to provide a clear
solution.
3. Allowed solution to
evaporate at room temp from
an open vial.
(1)
Slurry of (1) in toluene at 40° C. In progress --
crystalline solids
(B/E) embedded
in yellow oil
NaOH 1. Dissolved starting material In progress --
(1:1) in toluene.
A solution of 2. Added 1 eq of methanolic
29.2 mg/mL of NaOH.
NaOH in 3. Removed methanol and
methanol was water by azeotropic distillation.
used 4. Added heptane to the warm
toluene solution and allowed to
cool
Zn(OH)2 Added 2.0 mL API solution in Massive white Unique
(1:1) MeOH to base slurry in solids: small pattern

MeOH/H2O (8:1, v/v), agitated acicular clusters
16 hours: clear, pale yellow and rosettes (B/E)
liquid with ~10 small, opaque
chunks (B). Let stand ~2 days;
isolate solids.
Main supernatant: second crop Pale yellow Same
after ~4 days. solids: mix of pattern as
small aciculars 1st crop
and fibrous
Added ~1 mL ether to 0.2 mL Massive gel-like --
aliquot of supernatant. ppt on walls; B
with areas of E
Zn(OH)2 6 mg of zinc hydroxide was Yellow solid Amorphous
(2:1) suspended in a mixture of
MeOH/water (80:20, v/v).
0.25 ml of API solution (200 mg/ml)
in MeOH was added to
the suspension. Solution turned
clear after mixing. Kept at RT
for 2 days. Solvent was
evaporated under N2 stream.
The resulting yellow film was
suspended in ether, placed on a
slurry wheel at RT for 1 day.
Solvent was decanted, the
remaining solid was dried
under N2 stream.
Zn(OH)2 0.25 ml of API solution (200 mg/ml) Light yellow solid
Amorphous
(2:1) in EtOH was added to and dark yellow
7 mg of zinc hydroxide. 0.25 ml gel
of EtOH was added
subsequently. Sonicated, the
resulting turbid solution was
placed on a slurry wheel at RT
for 1 day. Solvent was
evaporated under N2 stream.
The resulting yellow film was
suspended in ether. Clear
solution decanted, the
remaining solid was dried
under N2 stream.
Zn(OH)2 0.25 ml of API solution (200 mg/ml) In progress --
(2:1) in IPA was added to ~7 mg
of zinc hydroxide. 0.25 ml
of IPA and 0.05 ml of water
were added subsequently.
Sonicated, resulted in clear
solution. FE at RT. To the
resulting yellow oil was added
ether. Place on a slurry wheel
at RT.
Zn(OH)2 0.25 ml of API solution (200 mg/ml) In progress --
(2:1) in ACN was added to
~7 mg of zinc hydroxide. 0.25 ml
of ACN and 0.05 ml of
water were added
subsequently. Sonicated,
resulted in clear solution. SE
at RT. To the resulting yellow
gel was added ether. Place on
a slurry wheel at RT.
Zn Acetate 24 mg of zinc acetate was Light yellow solid Amorphous
(1:1) added to 0.25 ml of API
solution (200 mg/ml) in
MeOH. 0.25 ml of MeOH
added, followed by 0.1 ml of
water. Zinc acetate dissolved.
The clear solution was set up
for FE at RT. The resulting
yellow oil was resuspended in
ether. Solvent was decanted,
the remaining solid dried under
N2.
Zn Acetate 12 mg of zinc acetate was Bright yellow Amorphous
(1:1) added to 0.25 ml of API solid
solution (200 mg/ml) in
MeOH. Zinc acetate dissolved.
The clear solution was set up
for FE at RT. The resulting
yellow oil was resuspended in
ether. Solvent was decanted,
the remaining solid dried under
N2.
Zn(OH)2 7 mg of zinc hydroxide and 4 mg Light yellow solid Amorphous
(2:1) of magnesium hydroxide
Mg(OH)2 were added to 0.25 ml of API
(2:1) solution (200 mg/ml) in
MeOH. Solid remained after
mixing. The suspension was
further mixed on a slurry wheel
for 2 days. Brown solution
with small amount of
precipitate on the bottom of the
vial. The solvent was
evaporated under N2 stream.
The resulting brown film was
suspended in ether. Light
yellow powdery solid formed.
Solvent was decanted, the
remaining solid was dried
under N2 stream.
Zn(OH)2 6 mg of zinc hydroxide and 4 mg Yellowish Disordered
(2:1) of magnesium hydroxide brown free flow Mg salt
Mg(OH)2 were added to 0.5 ml of API powder Form A
(2:1) solution (100 mg/ml) in THF.
Solution remained turbid after
sonication. The mixture was
further mixed on a slurry wheel
at RT for 3 days, resulted in
clear brown solution. The
solvent was evaporated under
N2 stream. The resulting brown
film was suspended in ether.
Yellowish brown solid formed.
Solvent was decanted, the
remaining solid was dried
under N2 stream.
Zn(OH)2 6 mg of zinc hydroxide and 4 mg Yellow solid Amorphous +
(2:1) of magnesium hydroxide Mg(OH)2
Mg(OH)2 were added to 0.5 ml of API peaks
(2:1) solution (100 mg/ml) in
ethanol. Solution remained
turbid after sonication. The
mixture was further mixed on a
slurry wheel at RT for 3 days.
White fine powdery precipitate
in yellow solution. The solvent
was evaporated under N2
stream. The resulting yellow
film was suspended in ether.
Light yellow solid formed.
Solvent was decanted, the
remaining solid was dried
under N2 stream.
Zn(OH)2 3 mg of zinc hydroxide and 2 mg Yellow solid Amorphous +
(4:1) of magnesium hydroxide Mg(OH)2
Mg(OH)2 were added to 0.5 ml of API peaks
(4:1) solution (100 mg/ml) in
ethanol. Solution remained
turbid after sonication. The
mixture was further mixed on a
slurry wheel at RT for 3 days.
White fine powder precipitated
on the bottom of the vial. The
solvent was evaporated under
N2 stream. The resulting
yellow film was suspended in
ether. Light yellow solid
formed. Solvent was decanted,
the remaining solid was dried
under N2 stream..

Example 2

Calcium Salt of (S)-3'-(OH)-DADFT-PE

[0261] The x-ray amorphous calcium salt was generated by mixing equal
molar ratio of API solution in methanol with base slurry in MeOH/H2O
(7.3:1, v/v). The filtered supernatant was slowly evaporated under
N2, followed by rotary evaporation. The calcium salt remained
physically unchanged when exposed to 75% RH for 3 days; however, when it
was stored at room temperature for 15 days, a color change was observed.
The aqueous solubility of the calcium salt is very low, less than 2
mg/ml.

Example 3

Magnesium Salt of (S)-3'-(OH)-DADFT-PE

[0262] The partial crystalline magnesium salt was generated by mixing
equal molar ratio of API solution in methanol with base slurry in
MeOH/H2O (11:1, v/v). The filtered supernatant was slowly evaporated
under N2, followed by rotary evaporation. Solid was generated by
anti-solvent precipitation in ether. A large scale preparation of the
magnesium was performed by mixing equal molar ratio of API solution in
methanol with base suspension in methanol/water. The filtered supernatant
was fast evaporated at ambient, and then dried under N2. Solid was
generated by anti-solvent precipitation in ether.

[0263] The solution proton NMR spectrum of the magnesium salt is
consistent with the chemical structure of the API. Significant peak
shifts were observed for all the protons in the API structure, implying
salt formation. A sharp peak at ˜3.3 ppm was assigned to water.
Solvent DMSO was also observed at ˜2.5 ppm.

[0264] The magnesium salt appears to be non-hygroscopic. It did not
deliquesce when exposed to 75% RH for 8 days, and the XRPD pattern
remained unchanged. The salt exhibits relatively high solubility in water
(≧48 mg/ml).

[0265] The DSC thermogram curve of the magnesium salt Form B (FIG. 10)
exhibits two broad endotherms. The major endotherm at approximately
79° C. is most likely due to the volatilization of water and is
associated with a TG weight loss of ˜16%. This weight loss is
significantly higher than that observed for Form A. The nature of the
minor endotherm at approximately 153° C. is unknown; however, it
may be related to a phase transition. A TG weight loss of 2.2% is
associated with this event.

[0266] The DVS data (FIG. 11) suggests that Form B is hygroscopic. The
material exhibits 10.8% weight loss upon equilibrium at 5% RH. During the
sorption step, the material exhibits a weight gain of 5.7% from 5% to 65%
RH and an additional 21.2% weight above 65% RH without reaching
equilibrium weight. This indicates that higher weight gains may be
possible. A weight loss of 26.6% was observed upon desorption.

[0267] The results of an initial polymorph screen crystallization
experiments of the amorphous form of the magnesium salt of
(S)-3'-(OH)-DADFT-PE are given below in Table 2, wherein FE stands for
fast evaporation, SE stands for slow evaporation and LC stands for low
crystallinity.

[0268] The results of an initial polymorph screen crystallization
experiments of (S)-3'-(OH)-DADFT-PE magnesium salt form A are given below
in Table 3, wherein FE stands for fast evaporation and SE stands for slow
evaporation.

[0270] The results of slow cool crystallization experiments of
(S)-3'-(OH)-DADFT-PE magnesium salt form A are given below in Table 5,
wherein SC stands for slow cool, RT stands for room temperature, LC
stands for low crystallinity, and IS stands for insufficient solid.

[0276] The X-ray amorphous sodium salt was generated by mixing equal molar
ratio of API solution in ethanol with base solution in water. Slow
evaporated sample was further dried in vacuum oven.

[0277] The proton NMR spectrum of the sodium salt confirms the integrity
of the API. Significant peak shifting and broadening were observed for
the aromatic protons. Peak shifting was also observed for protons in the
vicinity of the --COOH group, implying salt formation. A sharp peak at
˜3.3 ppm was assigned to water. Solvent DMSO was also observed at
˜2.5 ppm.

[0278] The sodium salt appears to be non-hygroscopic. It remained
physically unchanged when exposed to 75% RH for 3 days.

Example 5

Piperazine Salt of (S)-3'-(OH)-DADFT-PE

[0279] The low crystallinity piperazine salt was generated by mixing equal
molar ratio of API solution in ethanol with base solution in ethanol,
followed by slow and fast evaporation under N2. The piperazine salt
appears to be hygroscopic. It deliquesced when exposed to 75% RH for 3
days.

Example 6

Potassium Salt of (S)-3'-(OH)-DADFT-PE

[0280] Form A of the potassium salt was generated by mixing equal molar
ratio of API solution in methanol with base solution in methanol. Solid
salt was collected by anti-solvent precipitation in ether.

[0281] The DVS data of the potassium salt Form A (FIG. 4) suggest that the
potassium salt is extremely hygroscopic. The material exhibits a weigh
gain of 67.7% during the sorption step from 5% to 95% RH, and weigh loss
of 63.4% during the desorption step from 95% to 5% RH, resulted in
hygroscopic material (tacky, yellow, gel-like solids). A plateau was
observed in the absorption curve between 45 and 65% RH with an average
percentage weight loss of 8.7%, corresponding to 2 moles of water per
API.

[0282] Deliquescence was observed during DVS measurement. Complete
deliquesce was also observed when exposed to 75% RH for 3 days. The
post-DVS sample recrystallized to a new form, termed Form B, when exposed
to 53% RH for 11 days.

[0283] Potassium salt Form A exhibits relatively high aqueous solubility
(>48 mg/ml) and other test solvents.

[0284] Potassium salt Form B was obtained from post-DVS sample exposed to
53% RH as described above. Form B was also obtained by exposing Form A to
53% RH for 11 days at room temperature. Form B was also generated
directly from a mixture of methanol/water (54% RH) by fast cooling from
RT to refrigerator or from 60° C. to RT as shown below in Table
11.

[0285] The DVS data of the potassium salt Form B (FIG. 5) suggest that
Form B is extremely hygroscopic (FIG. 4). The material exhibits a weigh
gain of ˜70% during the sorption step from 5% to 95% RH, and weigh
loss of ˜66% during the desorption step from 95% to 5% RH, resulted
in deliquesced material. A plateau was observed in the absorption curve
between 35 and 65% RH with an average percentage weight gain of
˜8%, corresponding to 2 moles of water per API.

[0286] Form B appears to be unstable. Form conversion occurred when
exposed to low humidity (P2O5) or elevated temperature
(40° C.). Form B converted to a new form, namely Form C, when
exposed to P2O5 for 6 days. It desolvated into a mixture with
Form A when exposed to 40° C. for 6 days.

[0287] Form C was obtained by exposing Form B in P2O5 for 6
days. No further characterization data on this form.

Example 7

Abbreviated Polymorph Screen of (S)-3'-(OH)-DADFT-PE Potassium Salt

[0288] Potassium salt Form A was subjected to a brief polymorph screen. A
large scale preparation was conducted to generate salt for an abbreviated
polymorph screen. 3'-DADFT-PE.KOH salt was dissolved in any one of
acetonitrile, ethyl acetate/water, isopropyl alcohol, methyl ethyl
ketone, or tetrahydrofuran, and subjected to solvent evaporation (drying)
either at room temperature or in a convection or vacuum oven, at a
temperature from room temperature to 80° C., for up to 20 days.
The slow evaporation attempt from acetonitrile at 40° C. in a
convection oven was the only method that yielded appreciable solids.
Results are shown below in Table 12.

[0289] The thermograms of the potassium salt Form B are displayed in FIG.
6. The DSC curve exhibits a sharp endotherm with a signal maximum at
˜53° C., corresponding to a two-step weight loss observed in
the TG curve with a total weight loss of ˜6.0%. This weight loss is
consistent with the 6.7% weight gain observed during form conversion from
Form A to Form B.

[0291] The proton NMR spectrum of the zinc salt confirms the integrity of
the API. Significant peak shifting was observed for the aromatic protons
and protons in the vicinity of the --COOH group, implying salt formation.
A sharp peak at ˜3.3 ppm was assigned to water. Solvent DMSO was
also observed at ˜2.5 ppm.

[0292] The zinc salt appears to be non-hygroscopic. It remained physically
unchanged when exposed to 75% RH for 3 days.

[0294] Crystals of a potential Zinc salt of (S)-3'-(OH)-DADFT-PE were
prepared at SSCI, Inc. and submitted for single crystal structure
analysis. The structure was determined by single crystal X-ray
diffraction analysis conducted at the Crystallography Laboratory at
Purdue University. The single crystal data collection, structure solution
and refinement were not performed according to cGMP specifications.

[0295] The quality of the structure obtained is high, as indicated by the
R-value of 0.054 (5.4%). Usually R-values in the range of 0.02 to 0.06
are quoted for the most reliably determined structures. The molecule
observed in the asymmetric unit of the single crystal structure is
consistent with the proposed molecular structure provided in Scheme 1.
The asymmetric unit shown in FIG. 3 contains two (S)-3'-(OH)-DADFT-PE
molecules, two Zinc anions and two waters of hydration.

[0296] The Zinc ion is in the pocket consisting of the phenol, the amine
and the acid group (FIG. 3). The acid group is bridging two Zinc
molecules and the fifth coordination site is filled by a water molecule.

[0297] After a structure is solved the quality of the data should be
assessed for its inversion-distinguishing power of the Flack parameter,
this is done be an examination of the standard uncertainty (u) of the
Flack parameter, which is classified as: strong inversion-distinguishing
power. Compound is enantiopure and absolute structure can be assigned
directly from the crystal structure.

[0298] Therefore, the absolute configuration of the model in FIG. 3 is
correct. This structure contains a single chiral centers located at C33
(refer to FIG. 3, ORTEP drawing) which has been assigned as S
configuration. This is consistent with the proposed configuration.
Additional specifications are given below in Table 13.

[0299] Approximate solubilities are calculated based on the total solvent
used to give a solution based on visual inspection. Small aliquots of
solvent are added to a weighed sample with agitation. Actual solubilities
may be greater because of the volume of the solvent portions utilized or
a slow rate of dissolution. Solubilities are reported to the nearest
mg/mL. Simulated gastric fluid (SGF) was prepared according to the 2008
USP vol. 1, p 817 except without pepsin.

[0302] The API was dissolved in ACN:water (4:1), solid base was added, the
suspension was sonicated overnight at 37° C. The solids were
collected via vacuum filtration and dried in a vacuum oven. The calcium
salt is consistent with disordered material with a higher level of order
compared to magnesium salt candidate. The material, designated as Calcium
A, showed negligible aqueous solubility. No apparent deliquescence was
observed upon ˜75% RH stress.

[0303] XRPD data for the calcium salt exhibited two low angle peaks
suggesting a higher level of order compared to magnesium salt candidate
(FIG. 13). The salt candidate was prepared utilizing a 1:1 ratio of
calcium hydroxide to 4'-(OH)-DADFT-PE. Solution 1H NMR data for the
potential salt were not acquired due to its low solubility in organic
solvents.

Example 14

Lysine Salt of (S)-4'-(OH)-DADFT-PE

##STR00017##

[0305] Aqueous base was added to the API in EtOH forming a clear solution,
which was kept in a refrigerator. Following fast evaporation, isopropyl
alcohol was added, followed by sonication, yielding a hazy, sticky gel.
The material was heated to ˜65° C. and isopropyl alcohol was
added. Vacuum filtration yielded solids which were stored over
P2O5. Lysine salt candidate is consistent with crystalline
somewhat disordered lysine salt of 4'-(OH)-DADFT-PE with ˜1:1 ratio
of lysine to API. The material showed negligible aqueous solubility. No
apparent deliquescence was observed upon ˜75% relative humidity
stress however the salt became oily suggesting its hygroscopicity.

[0306] The lysine salt candidate was characterized by XRPD and solution
1H NMR spectroscopy. Overall, the data for the material are
consistent with crystalline, somewhat disordered lysine salt of
4'-(OH)-DADFT-PE with ˜1:1 ratio of lysine to API. XRPD pattern
exhibited resolution of peaks indicative of crystalline material with
some disorder consistent with Lysine A salt of 4'-(OH)-DADFT-PE (FIG.
13).

[0307] Solution 1H-NMR data are consistent with lysine salt of
4'-(OH)-DADFT-PE based on peak centered at ˜8.0 ppm, peaks at
˜3.2 ppm and ˜2.7 ppm and in the range of ˜1.8-1.3 ppm
attributable to lysine. The integral values suggest that the salt
contains approximately one mole of lysine per one mole of
4'-(OH)-DADFT-PE. Peak at ˜2.50 ppm is associated with partially
deuterated DMSO.

Example 15

Magnesium Salt of (S)-4'-(OH)-DADFT-PE

##STR00018##

[0309] The API was dissolved in ACN:water (4:1), solid base was added, the
resulting slurry was sonicated overnight at 37° C. Solids were
collected via vacuum filtration, and the filtrate was reduced via rotary
evaporation between ˜55 and ˜80° C. The resulting
magnesium salt candidate is consistent with amorphous or mesophasic
monohydrate of 4'-(OH)-DADFT-PE salt. The material exhibited substantial
aqueous solubility (˜60 mg/mL). No apparent deliquescence was
observed upon ˜75% RH stress however the salt showed a significant
water uptake (˜42.7 wt %) upon increasing relative humidity from
˜5% to ˜95% RH suggesting its hygroscopicity.

[0310] The magnesium salt candidate was prepared using a 1:1 ratio of
magnesium hydroxide to 4'-(OH)-DADFT-PE. It was characterized by XRPD,
thermogravimetry (TG), differential scanning calorimetry (DSC), moisture
sorption analysis and 1H NMR spectroscopy. Overall, the data for the
material are consistent with amorphous or mesophasic salt of
4'-(OH)-DADFT-PE possibly hydrated or containing water. The salt showed a
significant water uptake (˜42.7 wt %) upon increasing relative
humidity from ˜5% to ˜95% RH suggesting its hygroscopicity.

[0312] Solution 1H NMR data are consistent with formation of
4'-(OH)-DADFT-PE salt based on significant changes throughout the
spectrum. Considerable peak shifts were observed in ˜8-6 ppm,
˜4.2-3.0 ppm, and ˜1.6-1.3 ppm ranges while no peaks were
detected in ˜14-12 ppm range compared to free 4'-(OH)-DADFT-PE.
Additional small peaks (˜6.6 ppm, ˜2.3 ppm, ˜1.9 ppm
and ˜1.6-1.5 ppm.) were observed, likely due to unidentified
impurities. The spectrum also exhibited peak at ˜3.34 ppm
associated with water. Peak at ˜2.50 ppm is associated with
partially deuterated DMSO. Small peak at ˜2.54 ppm was observed due
to undeuterated DMSO.

[0313] Thermal data are consistent with solvated material or the material
containing solvent. TG data demonstrated a ˜4.0% weight loss
between ˜36 and ˜137° C. The weight loss is likely
attributable to a loss of approximately 1 mole of water per mole of API
based on the preparation conditions and 1H NMR data. The 1H NMR
spectrum of the material prepared in ethanol:water (1:1) mixture did not
exhibit peaks associated with ethanol, while peak attributable to water
was detected. A smaller ˜1.6% loss between ˜137° C.
and ˜195° C. followed by a sharp weight loss at
˜280° C. (onset) were observed likely due to decomposition.

[0314] The differential scanning calorimetry (DSC) curve demonstrated a
broad endotherm between ˜39.2° C. and ˜133.6°
C. with a peak maximum at ˜85.0° C. The event was observed
concurrently with the ˜4.0% TG loss and is likely associated with
desolvation. Broadened endotherm at ˜161.2° C. followed by a
small endothermic event at ˜173.7° C. (peak maxima) was
detected possibly due to melting accompanied by decomposition of the
material (FIG. 15).

[0315] Moisture sorption data showed ˜0.7 wt % loss upon
equilibration at ˜5% RH. A significant ˜22.0 wt % gain was
observed below ˜85% RH, above which the material gained additional
˜20.2 wt % with a total gain of ˜42.7 wt %. The equilibration
was not reached between ˜85% and ˜95% RH indicating that even
higher moisture uptake is possible. Partial desorption occurred with a
small hysteresis upon decreasing relative humidity to ˜5%
(˜41.2 wt % loss between ˜95% and ˜5% RH).

Example 16

N-methyl-D-glucamine (NMG) salt of (S)-4'-(OH)-DADFT-PE

##STR00019##

[0317] An ethanolic solution of the API was added to the base, then
sonicated giving a clear solution. Slow evaporation yielded a sticky
material, which was dried by blowing N2(g) across it. MeOH was
added. Following sonication, the addition of EtOAc yielded some
precipitation. Slurry for ˜5.5 hrs afforded viscous material, which
was washed with EtOAc, and isolated via vacuum filtration. NMG salt
candidate is consistent with disordered unsolvated NMG salt of
4'-(OH)-DADFT-PE with ˜1:1 ratio of NMG to API. The material
exhibited substantial aqueous solubility (˜60 mg/mL). No apparent
deliquescence was observed upon ˜75% RH stress however the salt
became oily. The salt also showed a significant water uptake (˜61.7
wt %) upon increasing relative humidity from ˜5% to ˜95% RH
suggesting its hygroscopicity.

[0319] XRPD patterns exhibited resolution of peaks indicative of a
disordered material consistent with NMG A salt of 4'-(OH)-DADFT-PE (FIG.
13). The XRPD pattern of the sample also displayed additional peak
associated with free NMG.

[0320]1H-NMR data are consistent with NMG salt of 4'-(OH)-DADFT-PE
based on peaks in ˜3.9-3.8 ppm and ˜3.0-2.8 ppm ranges, peak
centered at ˜4.7 ppm and peaks at ˜3.10 ppm and ˜2.48
ppm attributable to NMG. The integral values suggest that the salt
contains approximately one mole of N-methyl-D-glucamine per one mole of
4'-(OH)-DADFT-PE. Additional small peak at ˜1.9 ppm was observed,
likely due to unidentified impurity. Peak at ˜2.50 ppm is
associated with partially deuterated DMSO.

[0321] Thermal data are consistent with unsolvated material. TG data
demonstrated negligible weight loss above ˜222° C. Sharp
weight loss at ˜222° C. (onset) was observed likely due to
decomposition. The DSC curve exhibited a small endotherm at
˜92.3° C. followed by an endotherm at ˜109.5°
C. (peak maxima). The two consecutive events could be associated with
melting of the salt instantaneously followed by a melting and/or possible
recrystallization with melting of free N-methyl-D-glucamine present in
the salt. Heat fluctuations beginning at ˜180° C. were
observed likely due to decomposition (FIG. 17).

[0322] Moisture sorption data showed ˜0.5 wt % loss upon
equilibration at ˜5% RH. A significant ˜34.7 wt % gain was
observed below ˜85% RH, above which the material gained additional
˜27.0 wt % with a total gain of ˜61.7 wt %. The equilibration
was not reached between ˜65% and ˜95% RH indicating that even
higher moisture uptake is possible. Partial desorption occurred with a
small hysteresis upon decreasing relative humidity to ˜5%
(˜60.6 wt % loss between ˜95% and ˜5% RH).

Example 17

Tromethamine salt of (S)-4'-(OH)-DADFT-PE

##STR00020##

[0324] Base was added to an ethanolic solution of the API. A clear
solution was obtained by stifling at room temperature for ˜3 hr.
Fast evaporation of the solution yielded the tromethamine salt of the
API. Tromethamine salt candidate is consistent with crystalline
unsolvated tromethamine salt of 4'-(OH)-DADFT-PE with ˜1:1 ratio of
tromethamine to API. The salt exhibited significant aqueous solubility
(above ˜124 mg/mL) and showed no apparent deliquescence upon
˜75% RH stress. The salt showed a small water uptake (˜1.5 wt
%) below ˜65% RH above which it gained ˜50.3 wt % indicating
lower hygroscopicity compared to magnesium and NMG salt candidates.

[0326]1H-NMR data are consistent with tromethamine salt of
4'-(OH)-DADFT-PE based on additional peak centered at ˜3.42 ppm
attributable to tromethamine. The integral values suggest that the salt
contains approximately one mole of tromethamine per one mole of API.
Additional small peak at ˜1.9 ppm was observed, likely due to
unidentified impurities. The spectrum also exhibited peaks at ˜3.33
ppm and ˜2.50 ppm attributable to water and partially deuterated
DMSO, respectively.

[0327] Thermal data are consistent with unsolvated material. The DSC curve
demonstrated a sharp asymmetrical endotherm at ˜110.1° C.
(peak maximum) with a small shoulder prior the endotherm possibly due to
melting. Broad endotherm at ˜203.5° C. is likely associated
with decomposition of the material (FIG. 19).

[0328] Moisture sorption data showed a small loss of ˜0.7 wt % upon
equilibration at ˜5% RH. A small ˜1.5 wt % gain was observed
below ˜65% RH, above which the material gained ˜50.3 wt %
with a total gain of ˜51.8 wt %. The equilibration was not reached
above ˜75% RH indicating that higher moisture uptake is possible.
Partial desorption occurred with a small hysteresis upon decreasing
relative humidity to ˜5% (˜48.4 wt % loss between ˜95%
and ˜5% RH).

[0329] In the attempt to prepare a hydrated form of tromethamine salt
additional experiment was performed. Tromethamine A salt candidate was
subjected to a one day relative humidity stress. It was shown to become
oily upon ˜75% RH stress at elevated temperature. However one hour
drying over a desiccant resulted in crystalline material consistent with
Tromethamine A salt.

Example 18

Solubilities of Salts in Various Solvents

[0330] Approximate solubilities are calculated based on the total solvent
used to give a solution based on visual inspection. Small aliquots of
solvent are added to a weighed sample with agitation. Actual solubilities
may be greater because of the volume of the solvent portions utilized or
a slow rate of dissolution. Solubilities are reported in Table 16 to the
nearest mg/mL.

TABLE-US-00017
TABLE 16
Potential Salt of
(S)-4'-OH-DADFT Solvent Solubility
Calcium A Water <0.5
0.1N HCl in 3
Water
Lysine A Water <0.5
Magnesium A Water 60
NMG A Water 60
Tromethamine A Water >24
Water >124

[0335] In the iron clearing experiments the rats were given a single 50,
150, or 300 mol/kg dose of the drugs po and/or sc. The compounds were
administered as a solution in water, 300 mol/kg dose only or (2) as the
monosodium salt of the compound of interest (prepared by addition of the
free acid to 1 equivalent of NaOH). The chelators were given to the
monkeys po and sc at a dose of 150 μmol/kg. The drugs were prepared as
for the rats; 2 was given po and sc as a solution in water.

[0336] Calculation of Iron Chelator Efficiency.

[0337] ICE is calculated by dividing the actual amount of iron cleared by
a given compound by the theoretical amount that should be cleared. The
theoretical iron outputs of the chelators were generated on the basis of
a 2:1 ligand:iron complex. The efficiencies in the rats and monkeys were
calculated as set forth in Bergeron, R J et al., J. Med. Chem. 1999, 42,
2432-2440. Data are presented as the mean+the standard error of the mean;
p-values were generated via a one-tailed Student's 1-test in which the
inequality of variances was assumed; and a p-value of <0.05 was
considered significant.

[0339] Because there is a limited amount of chelatable iron available in
an animal at any given time, the iron clearance, and therefore
iron-clearing efficiency of a ligand, is saturable. The key to managing
this phenomenon can be found in the ferrokinetics and the dose-response
properties of the ligand. In this regard, the dose-response along with
the corresponding ferrokinetics of each compound given po were evaluated
in the non-iron-overloaded, bile duct-cannulated rodent model. Results
are shown below in Table 17.

[0341] A similar protocol was carried out to confirm consistence of
results and compare the effects of the compounds across species. Cebus
apella monkeys and male Sprague-Dawley rats were used, 3-8 per group.
Results are shown below in Table 18.

[0342] The above protocols and data are taken from Bergeron, R J et al.,
"Design, Synthesis, and Testing of Non-Nephrotoxic Desazadesferrithiocin
Polyether Analogues," J Med. Chem. 2008, 51(13), 3913-23. Additional data
pertaining to tissue distribution, toxicity, and pharmacokinetics can be
found in this publication.

Example 20

Salts of DADFT Polyethers as Lanthanide and Actinide Chelating Agents

[0343] The protocol employed in Rao L, Choppin G R, and Bergeron R J,
Radiochim. Acta. 88, 851-856 (2000) could be used, optionally with
adaptations clear to those of skill in the art, to ascertain the activity
of compounds according to the present invention as chelators of
lanthanides and actinides. Salts and polymorphs of Formula I are expected
to show efficacy in this assay.

[0344] The following compounds can generally be made using the methods
known in the art and described above. It is expected that these compounds
when made will have activity similar to those that have been made in the
examples above.

[0345] The notation below is intentionally free of assignment of ionic
character; salt are shown as acid compounds paired with bases. In this
manner, each structure is intended to represent the corresponding ions
that would be formed under a given set of conditions, such as, for
example, in aqueous solution. Typically, a base will ionically bond with
the carboxyl group(s) of one or more compounds and release one or more
molar equivalents of water. Under certain circumstances, a nitrogen may
be a site of acid salt formation. As those of skill in the art will
recognize, different ratios of counterions may form stable arrangements
and solid forms, including 1:1, 2:1, and 3:1 based on preferred oxidation
states of each ion, salt formation conditions (including solvent), etc.
All such forms are contemplated here.

[0346] From the foregoing description, one skilled in the art can easily
ascertain the essential characteristics of this invention, and without
departing from the spirit and scope thereof, can make various changes and
modifications of the invention to adapt it to various usages and
conditions.